Dry powder inhaler and system for drug delivery

ABSTRACT

A breath-powered, dry powder inhaler, a cartridge, and a pulmonary drug delivery system are provided. The dry powder inhaler can be provided with or without a unit dose cartridge for using with the inhaler. The inhaler and/or cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient, including, peptides and proteins such as insulin and glucagon-like peptide 1 for the treatment of diabetes and/or obesity. The dry powder inhaler is compact; can be provided in various shapes and sizes, colors, and comprises a housing, a mouthpiece, a cartridge placement area, and a mechanism for opening and closing the medicament cartridge. The device is easy to manufacture, provides a pre-metered single unit dose, it is relatively easy to use, and can be reusable or disposable.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/484,129 filed Jun. 12, 2009, which claims priority from U.S.Provisional Patent Application Ser. Nos. 61/157,506, filed Mar. 4, 2009,and 61/061,551, filed on Jun. 13, 2008, the contents of each of theseapplications are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to dry powder inhalers, cartridges fordry powder inhalers and a system for rapid drug delivery to thepulmonary tract, including dry powder medicament formulations comprisingactive agents for the treatment of disease such as diabetes and obesityfor use with the inhalers. In particular, the system can include a drypowder inhaler with or without a unit dose cartridge, and a drugdelivery formulation comprising, for example, a diketopiperazine and anactive ingredient such as peptides and proteins, including insulin andglucagon-like peptide 1.

All references cited in this specification, and their references, areincorporated by reference herein in their entirety where appropriate forteachings of additional or alternative details, features, and/ortechnical background.

BACKGROUND

Drug delivery systems for the treatment of disease which introduceactive ingredients into the circulation are numerous and include oral,transdermal, inhalation, subcutaneous and intravenous administration.Drugs delivered by inhalation are typically delivered using positivepressure relative to atmospheric pressure in air with propellants. Suchdrug delivery systems deliver drugs as aerosols, nebulized or vaporized.More recently, drug delivery to lung tissue has been achieved with drypowder inhalers. Dry powder inhalers can be breath activated orbreath-powered and can deliver drugs by converting drug particles in acarrier into a fine dry powder which is entrained into an air flow andinhaled by the patient. Drugs delivered with the use of a dry powderinhaler can no longer be intended to treat pulmonary disease only, butalso specific drugs can be used to treat many conditions, includingdiabetes and obesity.

Dry powder inhalers, used to deliver medicaments to the lungs, contain adose system of a powder formulation usually either in bulk supply orquantified into individual doses stored in unit dose compartments, likehard gelatin capsules or blister packs. Bulk containers are equippedwith a measuring system operated by the patient in order to isolate asingle dose from the powder immediately before inhalation. Dosingreproducibility requires that the drug formulation is uniform and thatthe dose can be delivered to the patient with consistent andreproducible results. Therefore, the dosing system ideally operates tocompletely discharge all of the formulation effectively during aninspiratory maneuver when the patient is taking his/her dose. However,complete discharge is not required as long as reproducible dosing can beachieved. Flow properties of the powder formulation, and long termphysical and mechanical stability in this respect, are more critical forbulk containers than they are for single unit dose compartments. Goodmoisture protection can be achieved more easily for unit dosecompartments such as blisters, however, the materials used tomanufacture the blisters allow air into the drug compartment andsubsequently the formulation loses viability with long storage.Additionally, dry powder inhalers which use blisters to deliver amedicament by inhalation can suffer with inconsistency of dose deliveryto the lungs due to variations in the air conduit architecture resultingfrom puncturing films or peeling films of the blisters.

Dry powder inhalers such as those described in U.S. Pat. Nos. 7,305,986and 7,464,706, which disclosure is incorporated herein by reference intheir entirety, can generate primary drug particles or suitableinhalation plumes during an inspiratory maneuver by deagglomerating thepowder formulation within a capsule. The amount of fine powderdischarged from the inhaler's mouthpiece during inhalation is largelydependent on, for example, the interparticulate forces in the powderformulation and the efficiency of the inhaler to separate thoseparticles so that they are suitable for inhalation. The benefits ofdelivering drugs via the pulmonary circulation are numerous and includerapid entry into the arterial circulation, avoidance of drug degradationby liver metabolism, ease of use, i.e., lack of discomfort ofadministration by other routes of administration.

Dry powder inhaler products developed for pulmonary delivery have metwith limited success to date, due to lack of practicality and/or cost ofmanufacture. Some of the persistent problems observed with prior artinhalers, include lack of ruggedness of device, propellants use todeliver the powder, consistency in dosing, inconvenience of theequipment, poor deagglomeration, and/or lack of patient compliance.Therefore, the inventors have identified the need to design andmanufacture an inhaler with consistent powder delivery properties, easyto use without discomfort, and discrete inhaler configurations whichwould allow for better patient compliance.

Further, drug delivery to the lungs for agents having systemic effectscan also be performed. Advantages of the lungs for delivery of systemicagents include the large surface area and the ease of uptake by thelung's mucosal surface. One problem associated with all of these formsof pulmonary drug delivery is that it is difficult to deliver drugs intothe lungs due to problems in getting the drugs past all of the naturalbarriers, such as the cilia lining the trachea, and in trying toadminister a uniform volume and weight of drug.

Accordingly, there is room for improvement in the pulmonary delivery ofdrugs.

SUMMARY

The present disclosure is directed to dry powder inhalers, cartridgesfor dry powder inhalers and a system for rapid drug delivery to thepulmonary tract, including dry powders comprising active agents for thetreatment of disease, including diabetes and obesity. The dry powderinhaler can be breath-powered, compact, reusable or disposable, hasvarious shapes and sizes, and comprises a system of airflow conduitpathways for the effective and rapid delivery of powder medicament. Inone embodiment, the inhaler can be a unit dose, reusable or disposableinhaler that can be used with or without a cartridge. By use without acartridge we refer to systems in which cartridge-like structures areintegral to the inhaler, as opposed systems in which a cartridge isinstalled for use by, for example, the user. In another embodiment, theinhaler can be a multidose inhaler, disposable or reusable that can beused with single unit dose cartridges installed in the inhaler orcartridge-like structures built-in or structurally configured as part ofthe inhaler.

The dry powder inhalation system comprises a dry powder inhalationdevice or inhaler with or without a cartridge, and a pharmaceuticalformulation comprising an active ingredient for pulmonary delivery. Insome embodiments delivery is to the deep lung (that is, to the alveolarregion) and in some of these embodiments the active agents is absorbedinto the pulmonary circulation for systemic delivery. The system canalso comprise a dry powder inhaler with or without a unit dosecartridge, and a drug delivery formulation comprising, for example,diketopiperazine and an active ingredient such as peptides and proteins,including insulin and glucagon-like peptide 1.

In one embodiment, the dry powder inhaler comprises a housing, amoveable member, and a mouthpiece, wherein the moveable member isoperably configured to move a container from a powder containmentposition to a dosing position. In this and other embodiments, themoveable member can be a sled, a slide tray or a carriage which ismoveable by various mechanisms.

In another embodiment, the dry powder inhaler comprises a housing and amouthpiece, structurally configured to have an open position, a closedposition and a mechanism operably configured to receive, hold, andreconfigure a cartridge from a containment position to a dispensing,dosing or dose delivery position upon movement of said inhaler from theopen position to the closed position. In versions of this embodiment,the mechanism can also reconfigure a cartridge installed in the inhalerfrom the dosing position to a containment position after use when theinhaler is opened to unload a used cartridge. In one embodiment, themechanism can reconfigure a cartridge to a disposable or discardingconfiguration after use. In such embodiments, the housing isstructurally configured to be moveably attached to the mouthpiece byvarious mechanisms including, a hinge. The mechanism configured toreceive and reconfigure a cartridge installed in the inhaler from acontainment position to the dosing position can be designed to operatemanually or automatically upon movement of the inhaler components, forexample, by closing the device from an open configuration. In oneembodiment, the mechanism for reconfiguring a cartridge comprises aslide tray or sled attached to the mouthpiece and movably attached tothe housing. In another embodiment, the mechanism is mounted or adaptedto the inhaler and comprises a geared mechanism integrally mountedwithin, for example, a hinge of the inhaler device. In yet anotherembodiment, the mechanism operably configured to receive and reconfigurethe cartridge from a containment position to a dosing position comprisesa cam that can reconfigure the cartridge upon rotation of, for example,the housing or the mouthpiece.

In an alternate embodiment, the dry powder inhaler can be made as asingle use, unit dose disposable inhaler, which can be provided with apowder container configured to hold a powder medicament, wherein theinhaler can have a first and a second configuration in which the firstconfiguration is a containment configuration and the secondconfiguration is a dosing of dispensing configuration. In thisembodiment, the inhaler can be provided with or without a mechanism forreconfiguring the powder container. According to aspects of the latterembodiment the container can be reconfigured directly by the user.

In yet another embodiment, an inhaler comprising a container mountingarea configured to receive a container, and a mouthpiece having at leasttwo inlet apertures and at least one exit aperture; wherein one inletaperture of the at least two inlet apertures is in fluid communicationwith the container area, and one of the at least two inlet apertures isin fluid communication with the at least one exit aperture via a flowpath configured to bypass the container area.

In one embodiment, the inhaler has opposing ends such as a proximal endfor contacting a user's lips or mouth and a distal end, and comprises amouthpiece and a medicament container; wherein the mouthpiece comprisesa top surface and a bottom or undersurface. The mouthpiece undersurfacehas a first area configured relatively flat to maintain a container in asealed or containment configuration, and a second area adjacent to thefirst area which is raised relative to the first area. In thisembodiment, the container is movable from the containment configurationto the dosing configuration and vice versa, and in the dosingconfiguration, the second raised area of the mouthpiece undersurface andthe container form or define an air inlet passageway to allow ambientair to enter the internal volume of the container or expose the interiorof the container to ambient air. In one embodiment, the mouthpiece canhave a plurality of openings, for example, an inlet port, an outlet portand at least one port for communicating with a medicament container in adispensing or dosing position, and can be configured to have integrallyattached panels extending from the bottom surface sides of the inhalerand having flanges protruding towards the center of the inhalermouthpiece, which serve as tracks and support for the container on themouthpiece so that the container can move along the tracks from thecontainment position to a dispensing or dosing position and back tocontainment if desired. In one embodiment, the medicament container isconfigured with wing-like projections or winglets extending from its topborder to adapt to the flanges on the mouthpiece panels. In oneembodiment, the medicament container can be moved manually by a userfrom containment position to a dosing position and back to thecontainment position after dosing, or by way of a sled, a slide tray, ora carriage.

In another embodiment, a single use, unit dose, disposable inhaler canbe constructed to have a sled incorporated and operably configured tothe mouthpiece. In this embodiment, a bridge on the sled can abut orrest on an area of the medicament container to move the container alongthe mouthpiece panel tracks from the containment position to thedispensing or dosing position. In this embodiment, the sled can beoperated manually to move the container on the mouthpiece tracks.

In one embodiment, the dry powder inhaler comprises one or more airinlets and one or more air outlets. When the inhaler is closed, at leastone air inlet can permit flow to enter the inhaler and at least one airinlet allows flow to enter a cartridge compartment or the interior ofthe cartridge or container adapted for inhalation. In one embodiment,the inhaler has an opening structurally configured to communicate withthe cartridge placement area and with a cartridge inlet port when thecartridge container is in a dosing position. Flow entering the cartridgeinterior can exit the cartridge through an exit or dispensing port orports; or flow entering the container of an inhaler can exit through atleast one of the dispensing apertures. In this embodiment, the cartridgeinlet port or ports is/are structurally configured so that all, or aportion of the air flow entering the interior of the cartridge isdirected at the exit or dispensing port or ports. The medicamentcontainer is structurally configured to have two opposing, relativelycurvilinear sides which can direct airflow. In this embodiment, flowentering the air inlet during an inhalation can circulate within theinterior of the container about an axis relatively perpendicular to theaxis of the dispensing ports, and thereby, the flow can lift, tumble andeffectively fluidize a powder medicament contained in the cartridge. Inthis and other embodiments, fluidized powder in the air conduit can befurther deagglomerated into finer powder particles by a change indirection or velocity, i.e., acceleration or deceleration of theparticles in the flow pathway. In certain embodiments, the change inacceleration or deceleration can be accomplished by changing the angleand geometries of, for example, the dispensing port or ports, themouthpiece conduit and/or its interfaces. In the inhalers describedherewith, the mechanism of fluidization and acceleration of particles asthey travel through the inhaler are methods by which deagglomeration anddelivery of a dry powder formulation is effectuated.

In particular embodiments, a method for deagglomerating and dispersing adry powder formulation comprises one or more steps such as tumblingwithin a primary container region started and enhanced by flow enteringthe container; a rapid acceleration of powder in the flow through thedispensing ports leaving the container; further accelerating the powderinduced by a change in direction or velocity as the powder exits thedispensing port; shearing of powder particles caught within a flowgradient, wherein the flow on the top of the particle is faster thanflow on bottom of the particle; deceleration of flow due to expansion ofcross-sectional area within the mouthpiece air conduit; expansion of airtrapped within a particle due to the particle moving from a higherpressure region to a lower pressure region, or collisions betweenparticles and flow conduit walls at any point in the flow passageways.

In another embodiment, a dry powder inhaler comprises a mouthpiece, asled, slide tray, or a carriage, a housing, a hinge, and a gearmechanism configured to effectuate movement of the sled or slide tray;wherein the mouthpiece and the housing are moveably attached by thehinge.

Cartridges for use with the dry powder inhaler can be manufactured tocontain any dry powder medicament for inhalation. In one embodiment, thecartridge is structurally configured to be adaptable to a particular drypowder inhaler and can be made of any size and shape, depending on thesize and shape of the inhaler to be used with, for example, if theinhaler has a mechanism which allows for translational movement or forrotational movement. In one embodiment, the cartridge can be configuredwith a securing mechanism, for example, having a beveled edge on thecartridge top corresponding to a matching beveled edge in an inhaler sothat the cartridge is secured in use. In one embodiment, the cartridgecomprises a container and a lid or cover, wherein the container can beadapted to a surface of the lid and can be movable relative to the lidor the lid can be movable on the container and can attain variousconfigurations depending on its position, for example, a containmentconfiguration, a dosing configuration or after use configuration.Alternatively the lid can be removable. An exemplary embodiment cancomprise an enclosure to hold medicament configured having at least oneinlet aperture to allow flow into the enclosure; at least one dispensingaperture to allow flow out of the enclosure; the inlet apertureconfigured to direct at least a portion of the flow at the dispensingaperture or at the particles approaching the dispensing aperture withinthe enclosure in response to a pressure gradient. The dispensingaperture or apertures and the intake gas aperture each independently canhave a shape such as oblong, rectangular, circular, triangular, squareand oval-shaped and can be in close proximity to one another. Duringinhalation, a cartridge adapted to the inhaler in a dosing positionallows airflow to enter the enclosure and mix with the powder tofluidize the medicament. The fluidized medicament moves within theenclosure such that medicament gradually exits the enclosure through thedispensing aperture, wherein the fluidized medicament exiting thedispensing aperture is sheared and diluted by a secondary flow notoriginating from within the enclosure. In one embodiment, the flow ofair in the internal volume rotates in a circular manner so as to lift apowder medicament in the container or enclosure and recirculate theentrained powder particles or powder mass in the internal volume of thecontainer promoting the flow to tumble prior to the particles exitingdispensing ports of the container or one or more of the inhaler inletports or air outlet or dispensing apertures, and wherein therecirculating flow, can cause tumbling, or non-vortical flow of air inthe internal volume acts to deagglomerate the medicament. In oneembodiment, the axis of rotation is mostly perpendicular to gravity. Inanother embodiment the axis of rotation is mostly parallel to gravity.The secondary flow not originating from within the enclosure furtheracts to de-agglomerate the medicament. In this embodiment, the pressuredifferential is created by the user's inspiration.

A cartridge for a dry powder inhaler, comprising: an enclosureconfigured to hold a medicament; at least one inlet port to allow flowinto the enclosure, and at least one dispensing port to allow flow outof the enclosure; said at least one inlet port is configured to directat least a portion of the flow entering the at least one inlet port atthe at least one dispensing port within the enclosure in response to apressure differential.

A unit dose cartridge for an inhaler comprising: a substantially flatcartridge top, arrow-like in configuration, having one or more inletapertures, one or more dispensing apertures, and two side panelsextending downwardly and each of the two side panels having a track; anda container moveably engaged to the track of the side panels of thecartridge top, and comprising a chamber configured to have a relativelycup-like shape with two relatively flat and parallel sides and arelatively rounded bottom, and interior surface defining an internalvolume; said container configurable to attain a containment position anda dosing position with the cartridge top; wherein in use with a drypowder inhaler during an inhalation a flow entering the internal volumediverges as it enters the internal volume with a portion of the flowexiting through the one or more dispensing apertures and a portion ofthe flow rotating inside the internal volume and lifting a powder in theinternal volume before exiting through the dispensing apertures.

In one embodiment, an inhalation system for pulmonary drug delivery isprovided, comprising: a dry powder inhaler comprising a housing and amouthpiece having an inlet and an outlet port, an air conduit betweenthe inlet and the outlet, and an opening structurally configured toreceive a cartridge; a cartridge mounting mechanism such as a sled; acartridge configured to be adapted to the dry powder inhaler andcontaining a dry powder medicament for inhalation; wherein the cartridgecomprises a container and a lid having one or more inlet ports or one ormore dispensing ports; the dry powder inhaler system in use has apredetermined airflow balance distribution through said cartridgerelative to total flow delivered to the patient.

In embodiments disclosed herewith, the dry powder inhaler systemcomprises a predetermined mass flow balance within the inhaler. Forexample, a flow balance of approximately 10% to 70% of the total flowexiting the inhaler and into the patient is delivered by the dispensingports or passed through the cartridge, whereas approximately 30% to 90%is generated from other conduits of the inhaler. Moreover, bypass flowor flow not entering and exiting the cartridge can recombine with theflow exiting the dispensing port of the cartridge within the inhaler todilute, accelerate and ultimately deagglomerate the fluidized powderprior to exiting the mouthpiece.

In the embodiments described herein, the dry powder inhaler is providedwith relatively rigid air conduits or plumbing system and high flowresistance levels to maximize deagglomeration of powder medicament andfacilitate delivery. Accordingly, effectiveness and consistency ofpowder medicament discharge is obtained from the inhaler after repeateduse since the inhaler are provided with air conduit geometries whichremain the same and cannot be altered. In some embodiments, the drypowder medicament is dispensed with consistency from the inhaler in lessthan about 3 seconds, or generally less than one second. In someembodiments, the inhaler system can have a high resistance value of, forexample, approximately 0.065 to about 0.200 (√kPa)/liter per minute.Therefore, in the system, peak inhalation pressure drops of between 2and 20 kPa produce resultant peak flow rates of about between 7 and 70liters per minute. These flow rates result in greater than 75% of thecartridge contents dispensed in fill masses between 1 and 30 mg. In someembodiments, these performance characteristics are achieved by end userswithin a single inhalation maneuver to produce cartridge dispensepercentage of greater than 90%. In certain embodiments, the inhaler andcartridge system are configured to provide a single dose by dischargingpowder from the inhaler as a continuous flow, or as one or more pulsesof powder delivered to a patient.

In one embodiment, a method for effectively deagglomerating a dry powderformulation during an inhalation in a dry powder inhaler is provided.The method can comprise the steps of providing a dry powder inhalercomprising a container having an air inlet, dispensing portscommunicating with a mouthpiece air conduit and containing anddelivering a formulation to a subject in need of the formulation;generating an airflow in the inhaler by the subject's inspiration sothat about 10 to about 70% of the airflow entering the inhaler entersand exits the container; allowing the airflow to enter the containerinlet, circulate and tumble the formulation in an axis perpendicular tothe dispensing ports to fluidize the formulation so as to yield afluidized formulation; accelerating metered amounts of fluidizedformulation through the dispensing ports and in the air conduit, anddecelerating the airflow containing fluidized formulation in themouthpiece air conduit of the inhaler prior to reaching the subject.

In another embodiment, a method for deagglomerating and dispersing a drypowder formulation for inhalation is provided, comprising the steps of:generating an airflow in a dry powder inhaler comprising a mouthpieceand a container having at least one inlet port and at least onedispensing port and containing a dry powder formulation; said containerforming an air passage between at least one inlet port and at least onedispensing port and the inlet port directs a portion of the airflowentering the container to at least one dispensing port; allowing airflowto tumble powder within the container in a substantially perpendicularaxis to the at least one dispensing port so as to lift and mix the drypowder medicament in the container to form an airflow medicamentmixture; and accelerating the airflow exiting the container through atleast one dispensing port. In one embodiment, the inhaler mouthpiece isconfigured to have a gradual expanding cross-section to decelerate flowand minimize powder deposition inside the inhaler and promote maximaldelivery of powder to the patient. In one embodiment, for example, thecross-sectional area of the oral placement region of an inhaler can befrom about 0.05 cm² to about 0.25 cm² over an approximate length ofabout 3 cm. These dimensions depend on the type of powder used with theinhaler and the dimensions of the inhaler itself.

A cartridge for a dry powder inhaler, comprising: a cartridge top and acontainer defining an internal volume; wherein the cartridge top has anundersurface that extends over the container; said undersurfaceconfigured to engage said container, and comprising an area to containthe internal volume and an area to expose the internal volume to ambientair.

In an alternate embodiment, a method for the delivery of particlesthrough a dry powder delivery device is provided, comprising: insertinginto the delivery device a cartridge for the containment and dispensingof particles comprising an enclosure enclosing the particles, adispensing aperture and an intake gas aperture; wherein the enclosure,the dispensing aperture, and the intake gas aperture are oriented suchthat when an intake gas enters the intake gas aperture, the particlesare deagglomerated, by at least one mode of deagglomeration as describedabove to separate the particles, and the particles along with a portionof intake gas are dispensed through the dispensing aperture;concurrently forcing a gas through a delivery conduit in communicationwith the dispensing aperture thereby causing the intake gas to enter theintake gas aperture, de-agglomerate the particles, and dispense theparticles along with a portion of intake gas through the dispensingaperture; and, delivering the particles through a delivery conduit ofthe device, for example, in an inhaler mouthpiece. In embodimentdescribed herein, to effectuate powder deagglomeration, the dry powderinhaler can be structurally configured and provided with one or morezones of powder deagglomeration, wherein the zones of deagglomerationduring an inhalation maneuver can facilitate tumbling of a powder by airflow entering the inhaler, acceleration of the air flow containing apowder, deceleration of the flow containing a powder, shearing of apowder particles, expansion of air trapped in the powder particles,and/or combinations thereof.

In another embodiment, the inhalation system comprises a breath-powereddry powder inhaler, a cartridge containing a medicament, wherein themedicament can comprise, for example, a drug formulation for pulmonarydelivery such as a composition comprising a diketopiperazine and anactive agent. In some embodiments, the active agent comprises peptidesand proteins, such as insulin, glucagon-like peptide 1, oxyntomodulin,peptide YY, exendin, analogs thereof, and the like. The inhalationsystem of the invention can be used, for example, in methods fortreating conditions requiring localized or systemic delivery of amedicament, for example, in methods for treating diabetes, pre-diabetesconditions, respiratory track infection, pulmonary disease and obesity.In one embodiment, the inhalation system comprises a kit comprising atleast one of each of the components of the inhalation system fortreating the disease or disorder.

The present disclosure also provides systems, microparticles and methodsthat allow for improved delivery of drugs to the lungs. Embodimentsdisclosed herein achieve improved delivery by providing fumaryldiketopiperazine (FDKP) microparticles with a trans isomer content ofabout 45 to about 65%. Microparticles with a trans isomer content inthis range exhibit characteristics beneficial to drug delivery to thelungs such as improved aerodynamic performance.

One embodiment disclosed herein comprises FDKP microparticles comprisinga trans isomer content of about 45 to about 65%. In another embodimentof the FDKP microparticles, the trans isomer content is from about 45 toabout 63%. In another embodiment of the FDKP microparticles, the transisomer content is from about 53 to about 65%. In another embodiment ofthe FDKP microparticles, the trans isomer content is from about 53 toabout 63%. In another embodiment of the FDKP microparticles, the transisomer content is from about 50 to about 56%. In another embodiment ofthe FDKP microparticles, the trans isomer content is from about 54 toabout 56%.

In another embodiment, the FDKP microparticles comprise a drug. Inanother embodiment of the FDKP microparticles, the drug is insulin. Inanother embodiment of the FDKP microparticles, the insulin content isfrom about 3 to about 4 U/mg.

Embodiments disclosed herein also include dry powders. In oneembodiment, the dry powders comprise FDKP microparticles comprising atrans isomer content of about 45 to about 65%. In another embodiment ofthe dry powders, the trans isomer content is from about 45 to about 63%.In another embodiment of the dry powders, the trans isomer content isfrom about 50 to about 63%. In another embodiment of the dry powders,the trans isomer content is from about 53 to about 65%. In anotherembodiment of the dry powders, the trans isomer content is from about 53to about 63%. In another embodiment of the dry powders, the trans isomercontent is from about 50 to about 56%. In another embodiment of the drypowders, the trans isomer content is from about 54 to about 56%.

In another embodiment of the dry powders, the FDKP microparticlescomprise a drug. In another embodiment of the dry powders, the drug isinsulin. In another embodiment of the dry powders, the insulin contentof the FDKP microparticles is from about 3 to about 4 U/mg.

Further embodiments concern drug delivery systems comprising an inhaler,a unit dose dry powder medicament container, and a powder comprising themicroparticles disclosed herein and an active agent.

Embodiments disclosed herein also include methods. One embodimentincludes a method of treating an insulin-related disorder comprisingadministering a dry powder described above to a person in need thereof.

Another embodiment disclosed herein includes a method of makingmicroparticles suitable for pulmonary administration as a dry powdercomprising: a) providing a solution of FDKP wherein the trans isomercontent is from about 45 to about 65%, b) providing a solution of avolatile acid, and c) mixing the solutions together in a high-shearmixer to produce the microparticles.

Also disclosed herein is a method for preparing FDKP microparticlescomprising recrystallizing FDKP from a solvent to obtain FDKPmicroparticles, wherein the trans-FDKP isomer content of themicroparticles is about 45% to about 65%, or about 53% to about 63%, orabout 54% to about 56%. Further embodiments include FDKP microparticlescomprising a drug, and having a manufacturing specification of about 53%to about 63% trans-FDKP isomer content, based on the total content ofFDKP.

Another embodiment disclosed herein includes a method of deliveringinsulin to a patient in need thereof comprising administering a drypowder comprising diketopiperazine microparticles disclosed herein tothe deep lung by inhalation of the dry powder by the patient. In aspectsof this embodiment particular features of an inhaler system arespecified.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a perspective view of an embodiment of a dry powderinhaler in a closed position.

FIG. 2 depicts a perspective view of the dry powder inhaler of FIG. 1showing the dry powder inhaler in a partially opened position.

FIG. 3 depicts a perspective view of the dry powder inhaler of FIG. 1showing the inhaler in a fully opened, cartridge loading/unloadingposition and depicting the interior compartment of the inhaler.

FIG. 4A depicts a perspective view of the inhaler in FIG. 1 showing theinhaler in a fully opened, cartridge loading/unloading position,depicting its internal surface including the interior surface of theinhaler mouthpiece. FIG. 4B depicts a perspective view of the dry powderinhaler of FIG. 4A showing the inhaler in the fully opened, cartridgeloading/unloading position and the cartridge configured for placementinto the inhaler. FIG. 4C is the inhaler shown in FIGS. 4A and 4Bshowing a cartridge loaded into the cartridge holder.

FIG. 5 depicts the dry powder inhaler of FIG. 1 with a cartridge and ina fully opened position, shown in mid-longitudinal section andcontaining a cartridge in the holder, wherein the cartridge container isin the containment position.

FIG. 6 depicts the dry powder inhaler of FIG. 1 with a cartridge and ina partially opened position shown in mid-longitudinal section andcontaining a cartridge in the holder, wherein the cartridge is in acontainment position.

FIG. 7 depicts the dry powder inhaler of FIG. 1 with a cartridge and ina closed position, shown in mid-longitudinal section and containing acartridge in the holder, wherein the cartridge is in a dosing position.

FIG. 8 depicts a top view of the dry powder inhaler of FIG. 1 in a fullyopened configuration and showing the inner compartment components of theinhaler.

FIG. 9 depicts a perspective view of an alternate embodiment of the drypowder inhaler in the closed or inhalation position.

FIG. 10 depicts the dry powder inhaler of FIG. 9 in an opened position,showing a cartridge installed in the cartridge holder, wherein thecartridge is in a containment position.

FIG. 11A and FIG. 11B depict the dry powder inhaler embodiment of FIG. 9in an opened (FIG. 11A) and closed (FIG. 11B) position, shown in amid-longitudinal section with the cartridge in the cartridge holder inthe containment position and dosing position, respectively.

FIG. 12 depicts a perspective view of an alternate embodiment of the drypowder inhaler in the closed position.

FIG. 13 depicts a perspective view of the dry powder inhaler embodimentof FIG. 12 in an open position showing the interior compartment of theinhaler.

FIG. 14 depicts the embodiment of FIG. 12 in an opened,loading/unloading position having a cartridge installed in the holder inthe containment position.

FIG. 15A depicts the embodiment of FIG. 12 showing the dry powderinhaler in the closed position as a cross-section through thelongitudinal axis. The geared mechanism for opening and closing acartridge and opening and closing the inhaler can be seen. FIG. 15Bdepicts the embodiment of FIG. 12 showing the dry powder inhaler in theclosed position as a cross-section through the mid-longitudinal axis.

FIG. 15C depicts an alternate embodiment of the inhaler of FIG. 12showing an isometric view of the inhaler in a closed position. FIGS.15D, 15E, 15F, 15G, and 15H depict side, top, bottom, proximal anddistal views, respectively, of the inhaler of FIG. 15C. FIG. 15I depictsa perspective view of the inhaler in FIG. 15C in an open configurationshowing a corresponding cartridge and a mouthpiece covering. FIG. 15Jdepicts an isometric view of the inhaler of FIG. 15I in an openconfiguration with a cartridge installed in the holder. FIG. 15K depictthe inhaler of FIG. 15C in cross-section through the mid-longitudinalaxis with a cartridge installed in the cartridge holder and in a dosingconfiguration, and the closed configuration FIG. 15J.

FIG. 16 illustrates a perspective view of an alternate embodiment of thedry powder inhaler in the closed position.

FIG. 17 illustrates the embodiment FIG. 16 in an opened,loading/unloading position having a cartridge installed in the cartridgeholder.

FIG. 18 illustrates the embodiment FIG. 16 in a closed, inhalationposition having a cartridge installed in the cartridge holder in adosing configuration.

FIG. 19 illustrates a perspective view of an alternate embodiment of adry powder inhaler for single use, showing the container in acontainment configuration.

FIG. 20 illustrates a perspective view of the inhaler shown in FIG. 19wherein the inhaler is in the dosing configuration, which allows air toflow through the interior of the powder containment cup.

FIG. 21 illustrates a perspective view of the inhaler shown in FIG. 19in mid-longitudinal section wherein the inhaler is in a containmentconfiguration.

FIG. 22 illustrates a perspective view of the inhaler shown in FIG. 20in longitudinal section wherein the inhaler is the dosing configuration.

FIG. 23 depicts a bottom view of the embodiment of FIG. 19, showing theundersurface of the dry powder inhaler components.

FIG. 24 illustrates a perspective view of yet another embodiment of adry powder inhaler for single use, showing the containmentconfiguration.

FIG. 25 illustrates a perspective view of the inhaler of FIG. 23 whereinthe dosing configuration, which allows air to flow through the interiorof the medicament container is shown.

FIG. 26 illustrates a perspective view of the inhaler shown in FIG. 24in mid-longitudinal section wherein the medicament container in acontainment or closed position is displayed.

FIG. 27 illustrates a perspective view of the inhaler shown in FIG. 24in mid-longitudinal section wherein the medicament container in a dosingposition is displayed.

FIG. 28 is a perspective and bottom view of the inhaler of FIG. 24,showing the undersurface components of the inhaler.

FIG. 29 illustrates a perspective view of yet an alternate embodiment ofa dry powder inhaler showing the containment configuration.

FIG. 30A and FIG. 30B illustrate perspective views of the inhaler ofFIG. 29 in an opened position and showing a cartridge installed in acontainment or closed position.

FIG. 31 illustrates a perspective view of the inhaler shown in FIG. 30in mid-longitudinal section in the open configuration wherein themedicament container in a containment position is displayed.

FIG. 32 illustrates a perspective view of the inhaler shown in FIG. 31in mid-longitudinal section wherein the medicament container in acontainment position is displayed and the mouthpiece section has beensecured with the housing.

FIG. 33 illustrates a perspective view of the inhaler shown in FIG. 29showing the inhaler in a dosing position.

FIG. 34 illustrates a perspective view of the inhaler shown in FIG. 33in mid-longitudinal section wherein the medicament container in a dosingposition is displayed.

FIG. 35 illustrates a perspective view of a cartridge embodiment for usewith the inhaler of FIG. 1 as also shown in FIG. 4B depicting thecartridge in a containment configuration.

FIG. 36 illustrates a top view of the cartridge embodiment of FIG. 35,showing the component structures of the cartridge top surface.

FIG. 37 illustrates a bottom view of the cartridge embodiment of FIG.35, showing the component structures of the cartridge undersurface.

FIG. 38A illustrates a perspective view of a cartridge embodiment ofFIG. 35 in mid-longitudinal cross-section and in a containmentconfiguration. FIG. 38B illustrates a perspective view of a cartridgeembodiment of FIG. 35 in a mid-longitudinal cross-section and in adosing configuration.

FIG. 39A depicts a perspective view of an alternate embodiment of acartridge in a containment configuration. FIG. 39B through 39F depictthe cartridge embodiment shown in FIG. 39A in a top, bottom, proximal,distal and side views, respectively. FIG. 39G depicts a perspective viewof the cartridge embodiment shown in FIG. 39A in a dosing configuration.FIGS. 39H and 39I are cross-sections through the longitudinal axis ofthe cartridge embodiment of FIGS. 39A and 39G, respectively.

FIG. 40 illustrates a perspective view of a cartridge embodiment for usewith the inhaler of FIG. 29 showing the cartridge in a containmentconfiguration.

FIG. 41 illustrates an exploded view of the cartridge embodiment of FIG.40, showing the component parts of the cartridge.

FIG. 42 illustrates a perspective view of a cartridge embodiment of FIG.40 in mid-longitudinal cross-section in a containment configuration.

FIG. 43 illustrates a perspective view of a cartridge embodiment of FIG.40 in a dosing configuration.

FIG. 44 illustrates a perspective view of a cartridge embodiment of FIG.38 in a mid-longitudinal cross-section and in a dosing configuration.

FIG. 45 illustrates a perspective view of an alternate cartridgeembodiment for use with a dry powder inhaler showing the cartridge in acontainment configuration.

FIG. 46A illustrates a perspective view of the cartridge embodiment ofFIG. 45 for use with a dry powder inhaler showing the cartridge in adosing configuration.

FIG. 46B illustrates a perspective view of a cartridge embodiment ofFIG. 45 in a mid-longitudinal cross-section and in a dosingconfiguration.

FIG. 47A illustrates a perspective view of an alternate cartridgeembodiment for use with a dry powder inhaler showing the cartridge in acontainment configuration.

FIG. 47B illustrates a perspective view of the cartridge embodiment ofFIG. 47A for use with a dry powder inhaler showing the cartridge in adosing configuration.

FIG. 48 illustrates a perspective view of an alternate embodiment of adry powder inhaler shown in an opened configuration.

FIG. 49 illustrates an exploded view of the inhaler embodiment of FIG.48 showing the inhaler component parts.

FIG. 50 illustrates a perspective view of the inhaler in FIG. 48 in theopen configuration and showing the type and orientation of a cartridgeto be installed in the inhaler holder.

FIG. 51 illustrates a perspective view of the inhaler in FIG. 50 in theopen configuration and showing a cartridge installed in the inhaler.

FIG. 52 illustrates a mid-longitudinal section of the inhaler depictedin FIG. 51 showing the cartridge container in the containmentconfiguration and in contact with the sled and the gear mechanism incontact with the sled.

FIG. 53 illustrates a perspective view of the inhaler in FIG. 50 in theclosed configuration and with a cartridge in the holder.

FIG. 54 illustrates a mid-longitudinal section of the inhaler depictedin FIG. 53 showing the cartridge container in the dosing configurationand the air flow pathway established through the container.

FIG. 55 is a schematic representation of the movement of flow within thepowder containment area of a dry powder inhaler as indicated by thearrows.

FIG. 56 is a schematic representation of an embodiment of a dry powderinhaler showing the flow pathways and direction of flow through theinhaler as indicated by the arrows.

FIG. 57 illustrates a perspective view of a multidose embodiment of adry powder inhaler.

FIG. 58 illustrates an exploded view of the inhaler embodiment of FIG.57 showing the inhaler component parts.

FIG. 59 illustrates a perspective bottom view of component part 958 ofthe inhaler depicted in FIG. 58.

FIG. 60 illustrates a perspective top view of component parts assembledof the inhaler depicted in FIG. 58.

FIG. 61 illustrates a perspective top view of component part 958 of theinhaler depicted in FIG. 58.

FIG. 62 illustrates a perspective top view of component parts of thehousing assembly of the inhaler depicted in FIG. 58.

FIG. 63 illustrates a perspective view of the cartridge disk system ofthe inhaler depicted in FIG. 58.

FIG. 64 illustrates a perspective view of the cartridge disk systemillustrated in FIG. 63 in cross-section.

FIG. 65 illustrates a perspective top view of the housing subassembly ofthe inhaler depicted in FIGS. 57 and 58.

FIG. 66 illustrates a perspective cross-sectional view of componentparts of the inhaler depicted in FIG. 58.

FIG. 67 illustrates a perspective view of the inhaler depicted in FIG.57 in cross-section.

FIG. 68 illustrates a perspective view of an alternate embodiment of amultidose dry powder inhaler.

FIG. 69 illustrates a perspective bottom view of the inhaler depicted inFIG. 68.

FIG. 70 illustrates a top view of the inhaler embodiment of FIG. 68showing the inhaler body and the mouthpiece.

FIG. 71 illustrates a front view of the inhaler depicted in FIG. 68.

FIG. 72 illustrates a side view of the inhaler depicted in FIG. 68.

FIG. 73 illustrates a perspective explode view showing the bottomcartridge tray removed with not all component parts depicted.

FIG. 74 illustrates an exploded view of the inhaler depicted in FIG. 68showing the gear drive system.

FIG. 75 illustrates a perspective view of cartridge disk system of theinhaler depicted in FIG. 68.

FIG. 76 illustrates a back view of cartridge disk system of the inhalerdepicted in FIG. 68.

FIG. 77 illustrates a front view of cartridge disk system of the inhalerdepicted in FIG. 68.

FIG. 78 illustrates a bottom view of cartridge disk system of theinhaler depicted in FIG. 68.

FIG. 79 illustrates a top view of seal disk of the inhaler depicted inFIG.

FIG. 80 illustrates a graph of measurements of flow and pressurerelationship based on the Bernoulli principle for an exemplaryembodiment of the resistance to flow of an inhaler.

FIG. 81 depicts the particle size distribution obtained with a laserdiffraction apparatus using an inhaler and cartridge containing a drypowder formulation for inhalation comprising insulin and fumaryldiketopiperizine particles.

FIG. 82 depicts aerodynamic powder performance as a function of % transisomer content;

FIG. 83 depicts steps in a synthetic scheme that can be controlled so asto produce FDKP with a trans isomer content of about 45 to about 65%;

FIG. 84 depicts % trans isomer content as a function of slow NaOHaddition during the saponification step of the scheme depicted in FIG.2;

FIG. 85 depicts % trans isomer content after trifluoroacetic acid (TFA)recrystallization using a fast cooling ramp;

FIG. 86 depicts a schematic of a process to manufacture insulin-loadedFDKP microparticles with a trans isomer content of about 45 to about65%; and

FIG. 87 depicts a response surface methodology analysis for trans isomercontent.

DETAILED DESCRIPTION

In embodiments disclosed herein, there is disclosed a dry powderinhaler, a cartridge for a dry powder inhaler and an inhalation systemfor delivering pharmaceutical medicaments to a patient via inhalation.In one embodiment, the inhalation system comprises a breath-powered drypowder inhaler, and a cartridge containing a pharmaceutical formulationcomprising a pharmaceutically active substance or active ingredient anda pharmaceutically acceptable carrier. The dry powder inhaler isprovided in various shapes and sizes, and can be reusable or for singleuse, easy to use, is inexpensive to manufacture and can be produced inhigh volumes in simple steps using plastics or other acceptablematerials. In addition to complete systems, inhalers, filled cartridgesand empty cartridges constitute further embodiments disclosed herein.The present inhalation system can be designed to be used with any typeof dry powder. In one embodiment, the dry powder is a relativelycohesive powder which requires optimal deagglomeration condition. In oneembodiment, the inhalation system provides a re-useable, miniaturebreath-powered inhaler in combination with single-use cartridgescontaining pre-metered doses of a dry powder formulation.

As used herein the term “a unit dose inhaler” refers to an inhaler thatis adapted to receive a single container a dry powder formulation anddelivers a single dose of a dry powder formulation by inhalation fromcontainer to a user. It should be understood that in some instancemultiple unit doses will be required to provide a user with a specifieddosage.

As used herein the term “a multiple dose inhaler” refers to an inhalerhaving a plurality of containers, each container comprising apre-metered dose of a dry powder medicament and the inhaler delivers asingle dose of a medicament powder by inhalation at any one time.

As used herein a “container” is an enclosure configured to hold orcontain a dry powder formulation, a powder containing enclosure, and canbe a structure with or without a lid.

As used herein a “powder mass” is referred to an agglomeration of powderparticles or agglomerate having irregular geometries such as width,diameter, and length.

As used herein, the term “microparticle” refers to a particle with adiameter of about 0.5 to about 1000 μm, irrespective of the preciseexterior or interior structure. However four pulmonary deliverymicroparticles that are less than 10 μm are generally desired,especially those with mean particles sizes of less than about 5.8 μm indiameter. Microparticles having a diameter of between about 0.5 andabout 10 microns can reach the lungs, successfully passing most of thenatural barriers. A diameter of less than about 10 microns is requiredto navigate the turn of the throat and a diameter of about 0.5 micronsor greater is required to avoid being exhaled. To reach the deep lung(or alveolar region) where most efficient absorption is believed tooccur, it is preferred to maximize the proportion of particles containedin the “respirable fraction” (RF), generally accepted to be about 0.5 toabout 5.7 microns, though some references use somewhat different ranges.Embodiments disclosed herein show that FDKP microparticles with a transisomer content of between about 45 to about 65% exhibit characteristicsbeneficial to delivery of drugs to the lungs such as improvedaerodynamic performance.

Respirable fraction on fill (RF/fill), representing the % of powder in adose that emitted from an inhaler upon discharge, is a measure ofmicroparticle aerodynamic performance. As described herein, a RF/fillscore of 40% or greater reflects acceptable aerodynamic performancecharacteristics.

It should be understood that specific RF/fill values can depend on theinhaler used to deliver the powder. Powders generally tend toagglomerate and crystalline DKP microparticles form particularlycohesive powders. One of the functions of a dry powder inhaler is todeagglomerate the powder. However deagglomeration is not typicallycomplete so that the particle size distribution seen when measuring therespirable fraction as delivered by an inhaler will not match the sizedistribution of the primary particles, that is the profile will beshifted toward larger particles. Although inhaler designs vary in theirefficiency of deagglomeration and thus the absolute value of RF/fillobserved using such different designs will also vary, it is expectedthat optimal RF/fill as a function of surface area (or other variablesimpacting aerodynamic performance) will be similar from inhaler toinhaler.

As used herein a “unit dose” refers to a pre-metered dry powderformulation for inhalation. Alternatively, a unit dose can be a singlecontainer having multiple doses of formulation that can be delivered byinhalation as metered single amounts. A unit dose cartridge/containercontains a single dose. Alternatively it can comprise multipleindividually accessible compartments, each containing a unit dose.

As used herein, the term “about” is used to indicate that a valueincludes the standard deviation of error for the device or method beingemployed to determine the value.

The present devices can be manufactured by several methods, however, inone embodiment, the inhalers and cartridges are made, for example, byinjection molding techniques, thermoforming, using various types ofplastic materials, including, polypropylene, cyclicolephin co-polymer,nylon, and other compatible polymers and the like. In certainembodiments, the dry powder inhaler can be assembled using top-downassembly of individual component parts. In some embodiments, theinhalers are provided in compact sizes, such as from about 1 inch toabout 5 inches in dimension, and generally, the width and height areless than the length of the device. In certain embodiments the inhaleris provided in various shapes including, relatively rectangular bodies,cylindrical, oval, tubular, squares, oblongs, and circular forms.

In embodiments described and exemplified herewith, the inhalerseffectively fluidize, deagglomerate or aerosolize a dry powderformulation by using at least one relatively rigid flow conduit pathwayfor allowing a gas such as air to enter the inhaler. For example, theinhaler is provided with a first air/gas pathway for entering andexiting a cartridge containing the dry powder, and a second air pathwaywhich can merge with the first air flow pathway exiting the cartridge.The flow conduits, for example, can have various shapes and sizesdepending on the inhaler configuration.

An embodiment of the dry powder inhaler is exemplified in FIGS. 1-8. Inthis embodiment, the dry powder inhaler has three configurations, i.e.,a closed configuration is illustrated in FIGS. 1 and 7, a partiallyopened configuration is illustrated in FIGS. 2 and 6 and an openconfiguration is illustrated in FIGS. 3-5 and 8. The dry powder inhaler100 as depicted in FIGS. 1-8 has a relatively rectangular body having aproximal end for contacting the user's lips or oral cavity and a distalend, with top and bottom sides, a housing 120, mouthpiece 130 andcarriage, slide tray or sled 117. FIG. 1 illustrates the dry powderinhaler in a closed position, wherein the mouthpiece 130 comprises abody 112 and has one or more air inlets 110 (see also FIGS. 5 and 7) andan oral placement section having an outlet 135. An air conduit runs thelength of the inhaler mouthpiece 130 from air inlet 110 to outlet 135.Mouthpiece 130 can be configured having a narrowing in the shape of anhourglass at approximately its mid to distal section to accelerateairflow, and then it is configured of a wider diameter at its proximalend, or oral placement section to decelerate airflow towards outlet oropening 135 (see FIG. 7). Air conduit 140 (FIG. 4A) has an opening 155for adapting an area or boss 126 of cartridge top 156 (FIG. 4B) and isin communication with a mounted cartridge 150 in the inhaler in theclosed position (FIGS. 6 and 7). When the inhaler is in a closed orinhalation position as shown in FIG. 1, body 112 encloses a portion ofthe housing 120 of the inhaler 100. FIG. 1 also depicts a cartridgeholder 115 extending downwardly from the inhaler body. In the embodimentof FIG. 1, the housing 120 is structurally configured to be relativelyrectangular in shape and has a bottom wall 123, side walls 124 withriblet projections 125 which facilitate a stable grip for opening andclosing the inhaler 100.

FIG. 2 is the dry powder inhaler embodiment depicted in FIG. 1, showingthe inhaler in a partially opened containment position, whereinmouthpiece 130 shows a portion of the housing 120 protruding slightlyoutwardly. In this position, mouthpiece 130 can pivot by angularrotation to an opened configuration for loading a cartridge, or can beclosed to a dosing configuration if a cartridge is contained in theholder, or for storage. In FIG. 2, a cartridge mounted in the cartridgeholder 115 is in a closed, powder containment configuration. FIG. 3illustrates a perspective view of the dry powder inhaler of FIG. 1,showing the inhaler in a fully opened, cartridge loading/unloadingposition and depicting the interior compartment areas of the inhaler. Asseen in FIG. 3, mouthpiece 130, in the fully opened position of theinhaler, can be relatively moved about 90° from vertical plane Y-Z to ahorizontal plane X-Z. As mouthpiece 130 rotates from the opened to theclosed position, aperture 155 (FIG. 4A) can engage cartridge boss 126(FIG. 4B) allowing exit or dispensing ports 127 to be in communicationand within the floor of the flow conduit 140 with a cartridge adapted inthe inhaler.

As illustrated in FIG. 3, housing 120 comprises the bottom portion ofthe inhaler body, which comprises a cartridge holder 115 in the shape ofa cup, a securing mechanism to secure the inhaler in the closedposition, such as snap 121, and an air inlet aperture 118 whichcommunicates with the mouthpiece air conduit 140 at opening 155 in themouthpiece floor without a cartridge in the holder 115 in the closedposition of the inhaler. With a cartridge installed in the inhaler andin the closed position, inlet aperture 118 communicates with thecartridge inlet port 119 when the cartridge 150 is in the dosingconfiguration (see FIG. 7). In the closed position of the inhaler, thesled 117 is configured at its proximal end to correspond in shape to airinlet aperture 118 of housing 120 so that the air inlet is notobstructed in the closed position of the inhaler. In this embodiment,movement of mouthpiece 130 from a partially opened to a closed positionis accomplished through a sliding motion in the X-Z plane, and movementof mouthpiece 130 from a partially open to a fully open configuration isangular rotating about the Z axis. To achieve full closure of theinhaler, mouthpiece 130 is moveable in the horizontal axis X and movesor slides distally relative to housing 120. In this manner, thetranslational movement of slide tray or sled 117 against the cartridgetop 156 of cartridge 150 being held in the cartridge container 115 (seeFIG. 4) moves and places the boss 126 over the cartridge container, sothat cartridge container 151 is under dispensing ports 127 and inalignment over mouthpiece opening 155. This translational movement alsoconfigures the cartridge 150 to form an opening or an air inlet 119 intothe container 151. A flow pathway is then established with air conduit140 and inlet 118 through dispensing ports 127. Cartridge boss 126 isstructurally configured to correspond and fit the opening 155 (FIG. 4A)in the waist section of the air conduit 140 of mouthpiece 130 so that itis within the internal wall of the air conduit 140.

FIGS. 4A-4C depict the perspective views of the dry powder inhaler ofFIG. 1 showing the inhaler in the fully opened, cartridgeloading/unloading position. FIG. 4A is a front view of the inhalershowing mouthpiece 130 comprising the top portion of the body of theinhaler; an aperture 155 relatively centrally located in the mouthpieceinner surface communicates with air conduit 140; an air inlet 110 and anair outlet 135 are in communication with the air conduit 140 of theinhaler 100. Housing 120 forms the bottom portion of the inhaler bodyand comprises a cartridge holder 115 and holds a slide tray or sled 117which moves relative to the housing 120. A hinge 160 (FIG. 4A) formed bya snap and a rod engages the slide tray or sled 117 onto mouthpiece 130.FIG. 4B illustrates the inhaler of FIG. 4A and a cartridge 150configured to be adaptable into inhaler 100. The inhaler is shown in thefully open position with a cartridge above the cartridge holdercontainer 115 yet to be installed in the inhaler; housing 120 comprisingan air aperture or inlet 118, slide tray or sled 117, which is engagedto mouthpiece 130 having aperture 155 and air inlet 110. Cartridge 150comprises a medicament container 151 and a top 156 comprising a boss 126with dispensing ports 127. The cartridge top 156 comprises a first area154 which is recessed such that its bottom wall is in contact withcontainer 151 top border and seals the container 151 in a containmentposition. While in this embodiment, first area 154 is recessed for easeof manufacturing, the first area 154 can have alternate designs as longas it forms an acceptable seal for containing a dry powder. A secondarea of cartridge top 156 contains boss 126 and this portion of thecartridge top is slightly raised and hollow in its undersurface so thatwhen the cartridge container 151 is moved to a dispensing position, thetop border of container 151 forms an opening or air inlet with cartridgetop 156 to create a passageway through the cartridge inlet and thedispensing ports. FIG. 4B shows cartridge 150 in a containment position,which is the position in which the cartridge is closed and does notallow a flow path to be established through its interior compartment. Asseen in the FIG. 4C, cartridge 150 is installed in inhaler 100 and theinhaler is in the opened configuration.

FIG. 5 also depicts the dry powder inhaler of FIG. 4C in a fully openedposition, shown in mid-longitudinal section and containing cartridge 150in the holder, wherein cartridge container 151 is in the containmentposition and fits into container holder 115. Cartridge top 156 andrecessed area 154 are clearly depicted as forming a tight seal with thecontainer 151. The area of the cartridge top 156 under the boss can beseen as concave-like in shape and raised when compared to the area 154.

FIG. 6 depicts the dry powder inhaler of FIG. 4A in a partially openedposition in mid-longitudinal section and containing cartridge 150 withcartridge container 151 installed in cartridge holder 115. In thisembodiment, cartridge container 151 is in a containment position; boss126 snuggly fitting in aperture 155 of airflow conduit 140, which allowsdispensing port 127 to be in fluid communication with air conduit 140.As seen in FIG. 6, sled or slide tray 117 abuts cartridge top 156, andthe mouthpiece and slide tray 117 can move as a unit so that thecartridge top can move over container 151 upon closure of the device toattain the dispensing position. In the closed or dispensing position,the securing mechanism illustrated by snaps 121 (FIG. 3) maintainhousing 120 and mouthpiece 130 securely engaged. In this embodiment,housing 120 can be disengaged from mouthpiece 130 by releasing the snapsand moving mouthpiece 130 over housing 120 in the opposite direction toattain a partially opened configuration which causes cartridge 150 to bereconfigured from the dosing position to the containment configuration.

Cartridge 150 can be movably configured from a containment position to adosing position within the inhaler upon reconfiguration of the inhalerunit to a closed position as shown in FIG. 7. In the dosing position,cartridge container 151 is in alignment with boss 126, and air inletport 119 is formed by cartridge container 151 and cartridge top 156,which is in communication with dispensing ports 127 establishing an airconduit through cartridge 150.

FIG. 7 further depicts a mid-longitudinal section of the dry powderinhaler of FIG. 1 in a closed position and ready for inhalation andcontaining cartridge 150 in holder 115, wherein the cartridge container151 is in a dosing position. As seen in FIG. 7, cartridge boss 126 isstructurally configured to fit in inhaler aperture 155 so that air flowexiting the cartridge through dispensing or exit ports 127 enters theflow path of air entering air conduit at 110. FIG. 7 also illustratescartridge air inlet 119 formed by cartridge top 156 and cartridgecontainer 151 in the dosing configuration and proximity of air inlet 119to dispensing ports 127. In one embodiment, boss 126 with dispensingports 127 are positioned at the narrowest section of air conduit 140 ofmouthpiece 130.

FIG. 8 depicts a top view of the dry powder inhaler of FIG. 1 in a fullyopened configuration and showing the inner compartment components of theinhaler. As seen in FIG. 8, mouthpiece 130 is moveably attached orarticulated to housing 120 by hinge assembly 160, via slide tray or sled117 which is engageably connected to mouthpiece 130 by hinge 160, 161and to housing 120 interior. Sled 117 is movable in the horizontal planeof housing 120 and can be prevented from moving further in the directionof the mouthpiece by flanges 134, which protrude outwardly and can bestopped by recess 137 of the housing. Cartridge container holder 115 isintegrally formed within the bottom wall of housing 120 which hasaperture 118 which allows ambient air into the inhaler to supply airflowinto the cartridge in a dosing position. Sled 117 is held within thehousing by, for example, protrusions or flanges 133 extending from theside walls of the housing into its interior space.

In another embodiment, a dry powder inhaler is provided with arelatively cylindrical shape. FIG. 9 through FIG. 11B illustrate thisembodiment, wherein the inhaler comprises a housing 220 integrallyattached to mouthpiece 230, and a sled or slide tray 217. In FIGS. 9 and10, sled 217 is depicted comprising outer shell 257 which is intelescopic arrangement and concentrically positioned and partiallycovering housing 220. Sled 217 further comprises a gripping mechanismsuch as ribs 225 on the outer surface of shell 257 for securely grippinginhaler sled 217 while sliding over housing 220 to open and close thedevice. Sled 217 further comprises groove 221 in its inner surface atits end facing the mouthpiece for engageably attaching with snap ring224 segments of mouthpiece 230 for securing the inhaler in a closedconfiguration.

As seen in FIG. 11A, sled 217 also comprises cartridge holder 215configured to receive cartridge 250. Cartridge holder 215 is integrallystructured with outer shell 257 so that movement of outer shell 257moves the cartridge holder while closing the inhaler. FIG. 11A alsoillustrates the positioning of cartridge 250 within the inhaler andwherein the cartridge can be seen as having top 256, boss 226,dispensing ports 227 and a container 251 in a containment position. Inthis embodiment, movement of sled 217 effectuates translation ofcartridge container 251 to the dosing position in alignment withdispensing ports 227 and configuration of inlet port 219 as seen in FIG.11B.

In this embodiment, housing 220 is tubular in shape and it isstructurally configured to have air inlet 210 with one or more airconduits, for example, air conduits such as, air conduits 245, 246.Surface projections or ribs 225 from the outer surface of sled shell 257allow for ease of gripping the inhaler device 200 in use. As seen inFIG. 9, the inhaler comprises mouthpiece portion 230 and housing 220,air inlet 210 and air outlet 235. As shown in FIG. 10, inhaler 200 canbe configured to an open configuration wherein a user can load and/orunload a cartridge. By gripping ribs 222 and 225, sled outer shell 257can be moved away from mouthpiece 230, and the cartridge holder can thenbe accessed. FIG. 10 shows inhaler 200 in an opened, cartridgeloading/unloading position and depicting sled 217 fully retracted frommouthpiece 230 to allow access to the internal compartment to load orunload a cartridge. FIG. 10 also illustrates cartridge 250 installed incartridge holder 215 of sled 217 and the mechanism such as outer shell257 for actuating and opening the cartridge to the airflow path uponengagement of the sled outer shell 257 in snap ring 224 of themouthpiece so that the device is in the closed, or inhalation position.Closing of the device is effectuated by translational movement of sled217 over the housing 220 and engagement of sled 217 with mouthpiece 230along horizontal axis X. As can be seen in FIG. 11B, the closing actionof the sled 217 moves the cartridge 250 until the cartridge top 256abuts mouthpiece recess surface 223, after which time continuousmovement of sled 217 to a closed position causes the container 251portion of cartridge 250 to be moved from a containment position to theopposite side of cartridge cover 256 so that dispensing ports 227 arealigned relatively over container or cup 251. An air inlet passage isthen created between container 251 and the cartridge top 256 which airinlet is in communication with the interior of container 251 and exit ordispensing ports 227 of boss 226.

FIG. 11A is a perspective view of a mid-longitudinal section of theembodiment of FIG. 10 in an open configuration. FIG. 11B is aperspective view of a mid-longitudinal section of the embodiment of FIG.10 in a closed, dosing configuration. As seen in FIGS. 11A and 11B, theinhaler comprises mouthpiece 230 having a frustoconical shape, airconduit 240 which is tapered to aperture 255 for engaging with cartridgeboss 226 on cartridge top 256 of cartridge 250 in a closed position.Mouthpiece 230 also comprises air outlet 235. FIGS. 10 and 11 also showthat housing 220 can be integrally attached to mouthpiece 230 andcomprises a snap ring segments 224 for engaging sled 217 in the closedposition. FIG. 11B shows inhaler 200 in the dosing configuration havingairway conduit 240 in communication with cartridge 250 throughdispensing port 227 and cartridge inlet 219. In the closedconfiguration, inhaler housing 220 protrudes beyond sled 217 and thecartridge container is translocated to a dosing position under boss 226.

In an alternate embodiment, there is provided a dry powder inhaler 300,comprising a mouthpiece, a sled or slide tray mechanism and a housing.In this embodiment illustrated in FIGS. 12 through 15, the inhaler isrelatively rectangular in shape with the mouthpiece 330 comprising thetop portion of inhaler body 305; an oral placement section 312; airinlet 310; air conduit 340 which extends from air inlet 310 to airoutlet 335. FIG. 12 illustrates the inhaler in the closed positionshowing the various features of the outside of inhaler 300 including,air channel 311 which can direct air into inlet port 375. An area 325for holding the inhaler is configured into inhaler body 305 for ease ofuse, and also serves as a surface to push or squeeze to release latches380.

FIG. 13 illustrates a perspective view of the embodiment of FIG. 12 inan open configuration, or cartridge loading and unloading position. Asillustrated in FIG. 13, mouthpiece 330 is engageably attached to housing320 by a hinge attached to gear mechanism 360, 363. Mouthpiece 330 hasan aperture 355 which is in fluid communication with air conduit 340; anair outlet 335 and flange 358 define a rectangular structure surroundingaperture 355. FIG. 13 also depicts housing 320 as comprising a cartridgeholder 315; with a section of sled 317 showing through the cartridgecontainer placement area, projections 353 for holding cartridge top 356in place and snaps 380 for closing the body portion of the inhalermouthpiece.

FIG. 14 illustrates a perspective view of the embodiment of FIG. 13 inan open configuration wherein a cartridge can be loaded or unloaded intothe cartridge holder. FIG. 14 illustrates an inhaler comprising amouthpiece 330 comprising the top portion of body 305 of the inhaler andhaving an aperture 355 relatively centrally located in the body andsurrounded by flange 358; mouthpiece oral placement section 312 isconfigured to extend from the inhaler body and has an air outlet forplacing in the oral cavity of a patient at dosing. The inhaler furthercomprises housing 320 which is engageably attached to mouthpiece 330 bya geared mechanism. In this embodiment, the geared mechanism is, forexample, a rack and pinion 363 (see also FIG. 15A) which allows for anangular movement of the mouthpiece relative to the housing. Rackmechanism 363 is engaged to sled 317 to effectuate movement of container351 of cartridge 350 to move slideably under the cartridge top and underthe cartridge boss 326 when the inhaler is in the closed position. FIG.14 also illustrates the position of cartridge 350 installed in holder315 and showing the internal compartment parts, including boss 326 withdispensing ports 327; gear mechanism 360, 363 and snaps 380 which assistin maintaining the device in a closed configuration. As seen in FIG. 13,mouthpiece 330 forms the inhaler body top portion, and comprises an oralplacement section 312 with air conduit 340 and air inlet 310 and airoutlet 335.

FIG. 15A and FIG. 15B depicts the embodiment of FIG. 12 showing the drypowder inhaler in the closed/inhalation position as cross-sectionsthrough the longitudinal axis with a cartridge 350 in the dosingposition inside the cartridge holder 315 of housing 320. FIG. 15Aillustrates gear mechanism 362, 363 engageably connected to sled 317 foropening and closing the inhaler and which simultaneously will move acartridge container to the dosing or dispensing position upon closingthe device.

FIG. 15B depicts the embodiment of FIG. 12 and FIG. 14 showing the drypowder inhaler in the closed/inhalation position as a cross-sectionthrough the mid-longitudinal axis. As can be seen, cartridge 350 is inthe dosing position, wherein boss 326 fits or engages with aperture 355of air conduit 340 to allow flow from dispensing ports 327 to exitcartridge 350 and merge into the flow path in conduit 340. FIG. 14 alsoshows cartridge top 359 securely held in position by projections 353 inthe cartridge placement area. FIGS. 15A and 15B show cartridge container351 configured in the dosing position and having air inlet port 356 inclose proximity to and in communication with dispensing ports 327. Sled317 abuts the cartridge container to maintain it in place forinhalation. In this embodiment, air inlet port 375 leading to cartridgeinlet 319 is configured to run beneath and parallel to air conduit 340.Movement of the cartridge in this embodiment is effectuated by theopening and closing of the mouthpiece 330 relative to the housingwherein the gear mechanism opens and closes the cartridge bytranslational movement of sled 317. As shown in FIG. 15B and in use,airflow enters the inhaler through air inlet 310 and simultaneously intoair inlet 375 which enters cartridge 350 through air inlet 319. In oneexample embodiment, the internal volume extending from inlet port 310 tooutlet port 335 is greater than about 0.2 cm³. In other exampleembodiments, the internal volume is about 0.3 cm³, or about 0.3 cm³, orabout 0.4 cm³ or about 0.5 cm³. In another example embodiment, thisinternal volume of greater than 0.2 cm³ is the internal volume of themouthpiece. A powder contained within cartridge container 351 isfluidized or entrained into the airflow entering the cartridge throughtumbling of the powder content. The fluidized powder then graduallyexits through dispensing port 327 and into the mouthpiece air conduit340 and further deagglomerated and diluted with the airflow entering atair inlet 310, prior to exiting outlet port 335.

FIGS. 15C-15K depict an alternate embodiment 302 of inhaler 300 depictedin FIGS. 12-15B. The inhaler comprises housing 320, mouthpiece 330, agear mechanism, and a sled and can be manufactured using, for example,four parts in a top down assembly manner. Mouthpiece 330 furthercomprises air conduit 340 configured to run along the longitudinal axisof the inhaler and having an oral placement portion 312, air inlet 310and air outlet 335 configured to have its surface angular or beveledrelative to the longitudinal axis of the air conduit, and cartridge portopening 355 which is in fluid communication with housing 320 and/or acartridge installed in housing 320 for allowing airflow to enter airconduit 340 from the housing or from a cartridge installed in theinhaler in use. FIG. 15C illustrates inhaler 302 in isometric view in aclosed position having a more slender body 305 than inhaler 300 formedby housing 320 and cover portion 308 of mouthpiece 330, which extendsover and engages housing 320 by a locking mechanism 312, for example, aprotrusion. FIGS. 15D, 15E, 15F, 15G, and 15H depict side, top, bottom,proximal and distal views, respectively, of the inhaler of FIG. 15C. Asshown in the figures, inhaler 302 comprises mouthpiece 330 having anoral placement section 312, an extended portion configured as a cover308 that can attach to housing 320 at least one location as shown inFIG. 15J. Mouthpiece 330 can pivot to open from a proximal position froma user's hands in an angular direction by hinge mechanism 313. In thisembodiment, inhaler 302 is configured also to have a gear mechanism 363as illustrated in FIG. 15J. Gear mechanism 317 can be configured withthe mouthpiece as part of the hinge mechanism to engage housing 320,which housing can also be configured to engage with sled 317. In thisembodiment, sled 317 is configured with a rack which engages thegearwheel configured on the hinge mechanism. Hinge mechanism 363 allowsmovement of mouthpiece 330 to an open or cartridge loadingconfiguration, and close configuration or position of inhaler 302 in anangular direction. Gear mechanism 363 in inhalers 300, 302 can actuatethe sled to allow concurrent movement of sled 317 within housing 320when the inhaler is effectuated to open and close by being integrallyconfigured as part of gear mechanism 363. In use with a cartridge, theinhaler's gear mechanism 363 can reconfigure a cartridge by movement ofsled 317 during closing of the inhaler, from a cartridge containmentconfiguration after a cartridge is installed on the inhaler housing, toa dosing configuration when the inhaler is closed, or to a disposableconfiguration after a subject has effectuated dosing of a dry powderformulation. In the embodiment illustrated herein, the hinge and gearmechanism are provided at the distal end of the inhaler, however, otherconfigurations can be provided so that the inhaler opens and closes toload or unload a cartridge as a clam.

In one embodiment, housing 320 comprises one or more component parts,for example, a top portion 316 and a bottom portion 318. The top andbottom portions are configured to adapt to one another in a tight seal,forming an enclosure which houses sled 317 and the hinge and/or gearmechanisms 363. Housing 320 is also configured to have one or moreopenings 309 to allow air flow into the interior of the housing, alocking mechanism 313, such as protrusions or snap rings to engage andsecure mouthpiece cover portion 308 in the closed position of inhaler302. Housing 320 is also configured to have a cartridge holder orcartridge mounting area 315 which is configured to correspond to thetype of cartridge to be used with the inhaler. In this embodiment, thecartridge placement area or holder is an opening in the top portion ofhousing 320 which opening also allows the cartridge bottom portion orcontainer to lie on sled 317 once a cartridge is installed in inhaler302. The housing can further comprise grasping areas 304, 307 configuredto aid a user of the inhaler to firmly or securely grip the inhaler toopen it to load or unload a cartridge. Housing 320 can further compriseflanges configured to define an air channel or conduit, for example, twoparallel flanges 303 which are also configured to direct air flow intothe inhaler air inlet 310 and into a cartridge air inlet of thecartridge air conduit positioned in the inhaler. Flanges 310 are alsoconfigured to prevent a user from obstructing inlet port 310 of inhaler302.

FIG. 15I depicts an isometric view of the inhaler of FIG. 15C in an openconfiguration with mouthpiece covering, for example, cap 342 andcartridge 170 which are configured to correspond to the cartridgemounting area and allow a cartridge to be installed in cartridge holder315 for use. In one embodiment, reconfiguration of a cartridge from acontainment position, as provided after manufacturing, can beeffectuated once the cartridge is installed in cartridge holder 315,which is configured within housing 320 and to adapt to the inhaler sothat the cartridge has the proper orientation in the inhaler and canonly be inserted or installed in only one manner or orientation. Forexample, cartridge 170 can be configured with locking mechanism 301 thatmatches a locking mechanism configured in the inhaler housing, forexample, the inhaler mounting area, or holder can comprise a bevelededge 301 which would correspond to a beveled edge 180 on the cartridgeof, for example, cartridge 170 to be installed in the inhaler. In thisembodiment, the beveled edges form the locking mechanism which preventsthe cartridge from popping out of holder 315 during movement of sled317. In one particular embodiment illustrated in FIGS. 15J and 15K, thecartridge lid is configured with the beveled edge so that it remainssecure in the housing in use. FIGS. 15J and 15K also show rack mechanism319 configured with sled 317 to effectuate movement of a cartridgecontainer 175 of cartridge 170 slideably under the cartridge top toalign the container under the cartridge top undersurface configured tohave dispensing port in a closed dosing position or configuration of theinhaler when inhaler 302 is ready for dosing a user. In the dosingconfiguration, an air inlet port forms by the border of the cartridgetop and the rim of the container, since the undersurface of thecartridge top is raised relative to the containment undersurface. Inthis configuration, an air conduit is defined through the cartridge bythe air inlet, the internal volume of the cartridge which is exposed toambient air and the openings in the cartridge top or dispensing port inthe cartridge top, which air conduit is in fluid communication with airconduit 340 of the mouthpiece.

Inhaler 302 can further include a mouthpiece cap 342 to protect the oralplacement portion of the mouthpiece. FIG. 15K depict the inhaler of FIG.15C in cross-section through the mid-longitudinal axis with a cartridgeinstalled in the cartridge holder and in an open configuration, and inthe closed configuration FIG. 15K.

FIG. 15J illustrates the position of cartridge 350 installed in holderor mounting area 315 and showing the internal compartment parts,including boss 326 with dispensing ports 327; gear mechanism 360, 363and snaps 380 which assist in maintaining the device in a closedconfiguration.

In yet another embodiment, dry powder inhaler 400 is disclosed having arelatively round body and comprising mouthpiece 430; cartridge holdersection 415 and housing 420 as illustrated in FIGS. 16-18. FIG. 16illustrates a perspective view of an alternate embodiment of the drypowder inhaler in the closed position, wherein mouthpiece 430 comprisesthe top portion of the body of the inhaler and housing 420 comprises thebottom portion of the inhaler in the dosing position. Mouthpiece 430also comprises oral placement section 412 having air outlet port 435.

FIG. 17 illustrates the embodiment of FIG. 16 in an opened,loading/unloading configuration showing cartridge 450 seated incartridge holder 415, showing top 456 of cartridge 450. In thisembodiment, the mechanism for actuating movement of cartridge 450 from acontainment position to an open configuration is, for example, a cam.Handle or lever 480 containing cartridge 450 can be moved by rotation oflever 480 to the closed position. In the closed position, cartridge 450within the lever 480 is moved under oral placement portion 412 ofmouthpiece 430.

FIG. 18 illustrates a mid-longitudinal section of the embodimentdepicted in FIG. 16 in a closed, inhalation position having cartridge450 installed in cartridge holder 415 in an open configuration. As seenin FIG. 18, in the cartridge dosing configuration, air inlet 459 isformed or defined by a gap between cartridge top 456 and container 451,which is in communication with dispensing ports 427 on boss 426.Dispensing ports 427 are in fluid communication with air conduit 440,thereby during an inhalation maneuver, airflow entering air conduit 440from cartridge 450 exits the cartridge and combines with airflow in theair conduit entering air inlet 410 and a flow is swept in the directionof air outlet 435.

FIG. 19 through FIG. 28 illustrate two alternative embodiments of thedry powder inhaler. In these embodiments, the dry powder inhaler isstructurally configured for single use as a unit dose inhaler andcartridge assembled together into a disposable, non-reusable unit. Theinhalers in this embodiment are manufactured to contain the desiredpre-metered, unit dose, drug formulation within the formed cartridgecontainer. In this embodiments, the container is also capable ofmovement from a containment position to a dosing or dispensingconfiguration.

FIGS. 19-23 illustrate perspective views of an embodiment of a drypowder inhaler for single use. FIG. 19 shows the inhaler in acontainment configuration. In this embodiment, inhaler 500 comprises atop surface 563 and a bottom or undersurface 562; a mouthpiece 530 and amounted cartridge assembly or sled 590. Mouthpiece 530 has an elongatedshape and it is structurally configured with an air inlet 510 and an airoutlet port 535. An air conduit extends from air inlet 510 to air outlet535 which creates a secondary pathway for airflow entering inhaler 500during inhalation.

FIG. 20 illustrates a perspective view of the inhaler embodiment shownin FIG. 19, wherein the inhaler is in the dose configurationestablishing a flow pathway through the interior of the cartridge andthe dispensing ports wherein the inhaler is ready for use. FIG. 20depicts mouthpiece 530 having an increasingly wider cross-sectional areaof air conduit 540 from air inlet port 510 to air outlet port 535, beingnarrower at the inlet port end 510. Mouthpiece 530 also is structurallyconfigured to have side extension or panels 532 integrally extendingfrom the walls of mouthpiece conduit 540 which support sled 590. A spacebetween the mouthpiece air conduit wall 540 and the panel is providedwhich allows the sled 590 to slide over mouthpiece 530. Sled 590 has afirst bridge 567 spanning mouthpiece 530 on the top side, and has wingsor flanges 565 which allow manual gripping or grasping of the sled 590to configure the device from the containment to the dose position, andvice versa.

FIG. 21 illustrates a perspective view of the inhaler shown in FIG. 19in mid-longitudinal section in a containment position. In FIG. 21,cartridge container 551 is integrally adapted to the mouthpiece 530 sothat it is flushed and sealed against the surface of mouthpiece 530.Container 551 has wing-like structures that can be suspended andmoveable on tracts configured on the bottom surface of the mouthpiecepanels or extensions 532. The mouthpiece panels 532 are structurallyconfigured so that movement of container 551 is contained within panels532. FIG. 23 depicts undersurface 562 showing sled 590 configured tohave a second bridge 568 on the bottom side of inhaler 500 which can beconfigured to be in contact with container 551 for translationalmovement from the containment position to the dispensing or dosingposition. When sled 590 is moved towards inlet port 510, it carriescontainer 551 translationally to an open position and for alignment withdispensing ports 527 located in the floor of mouthpiece conduit 540. Inthe dosing configuration an inlet port is defined by the container rimand the mouthpiece undersurface to allow the internal volume to beexposed to ambient air. The dosing configuration also defines an airconduit between the inlet port, the internal volume of the container andthe dispensing ports to allow a flow to transit the container anddeliver a powder dose contained therein. Full alignment of container 551and dispensing ports 527 is achieved by moving the sled from thecontainment position to the dose position until the sled cannot movefurther in panel 532. FIG. 22 illustrates a perspective view of theinhaler shown in FIG. 20 in longitudinal section wherein the cartridgeis in the open or dosing position. In this configuration, a primary airpassage is established through the container as represented by inlet 556and dispensing port 527 with the container's internal volume. Asecondary flow passage is provided by mouthpiece conduit 540 from airinlet 510 to outlet 535 which is configured to provide a flow thatimpinges a flow exiting the dispensing ports to prove shear force andpromote deagglomeration of powder particles as they exit the dispensingports in use.

FIGS. 24-28 illustrate perspective views of yet another embodiment of adry powder inhaler for single use. In this embodiment, the inhaler 600has top surface 665 and bottom or undersurface 652 and comprisesmouthpiece 630 and container 651. FIG. 24 shows the container 651component in a containment configuration. In this embodiment, inhaler600 comprises mouthpiece 630 and mounted container 651 attached andmoveable relative to mouthpiece 630. Mouthpiece 630 has an elongatedshape and it is structurally configured with air inlet 610 and airoutlet port 635. An air conduit 640 extends from air inlet 610 to airoutlet 635 which is configured to create an additional or secondarypathway for airflow entering inhaler 600 during inhalation. FIG. 28shows mouthpiece 630 undersurface 652 which is configured with parallelside panels 612 at each side of the inhaler, configured to haveprojections or wings 653 for holding or securely gripping inhaler 600.Panels 612 are configured on their bottom ends with, for example, aflange to form a track for adapting and supporting side wings 666 on thecartridge container. FIG. 26 shows undersurface 652 of mouthpiece 630configured to hold the cartridge container in a sealed or containmentposition, and in this area, undersurface 652 is flushed against the topof cartridge container 651. Mouthpiece undersurface 615 is configured tohave a concave-like or hollow form so that when the container 651 ismoved to the inhalation or dosing position, air inlet 656 is created bythe container wall and the mouthpiece undersurface. An air flow pathwayis then established between inlet 656 and dispensing port 627.

FIG. 25 illustrates a perspective view of the inhaler shown in FIG. 24wherein the cartridge component is in the open configuration whichallows air to flow through the interior of the cartridge. FIG. 26illustrates a perspective view of the inhaler shown in FIG. 24 inmid-longitudinal section wherein container 651 is in the containmentposition. FIG. 27 illustrates a perspective view of the inhaler shown inFIG. 25 in mid-longitudinal section wherein the cartridge is in the openor dosing position. In a dosing configuration, container inlet port 656forms an air conduit with dispensing port 627 which is in communicationwith mouthpiece air conduit 640. Container 651 is supported by containerwings 666 through parallel tracks and the undersurface of the device.

Perspective views of an alternate embodiment of the dry powder inhalerare illustrated in FIGS. 29-34. In this embodiment, the inhaler can bein a closed-containment configuration and in a closed-dosingconfiguration. The figures depict the inhaler with or without acartridge, and depicting its relatively circular, disk-like body formedby a portion of mouthpiece 730 and housing 720, and having top andbottom surfaces. Mouthpiece 730 has an inlet port 710 and outlet port735, and opening 755 in its undersurface. Mouthpiece 730 is configuredto define the top portion 731 of the inhaler body and is movablyattached by a hinge 760, which allows the inhaler to be opened from acontainment position in an angular motion to load and unload acartridge. Mouthpiece 730 can also be rotatably movable relative tohousing 720 from a containment position to a closed, dosing positing ofthe inhaler through and angle of about 180°. FIG. 30A also illustrates amedicament cartridge 780 for use with this inhaler which is alsodepicted in FIGS. 40 through 44 and comprises a top or lid 756 andcontainer 751 configured to fit in holder 715 within housing 720.Housing 720 comprises cartridge holder 715 and is configured to definethe bottom portion of the inhaler body. FIGS. 30A, 30B and 31 show theinhaler in a containment configuration wherein mouthpiece 730 and thehousing 720 are can allow a cartridge to be loaded. When a medicamentcartridge is installed in holder 715 as illustrated in FIGS. 30B, 31, 32and 34 mouthpiece 730 has an engagement mechanism with the housing suchas a snap ring and can rotate relative to housing 720. FIG. 30Aadditionally shows that mouthpiece 730 can engage with an intermediatestructure or rotator 717 which is configured to adapt to the housing 720by a ring and groove mechanism and is configured to hold a cartridge. Asshown in FIG. 32, mouthpiece 730 also engages cartridge top 756 definingan air conduit between the cartridge top and mouthpiece air conduit 740,wherein movement of mouthpiece 730 and cartridge top 756 move togetherrelative to housing 720 to position cartridge boss 726 over container751, aligning dispensing ports 727 over container 751 and holder 715. Aninlet port 719 is defined by the cartridge top 756 over container 751 toallow air entry into the cartridge 780 and through the dispensing ports727 in a dosing configuration. FIGS. 33 and 34 illustrate the inhaler ina closed-dosing configuration wherein rotation of the inhaler overcartridge container 751 also defines an air flow communication betweenan inhaler inlet port 710 of the inhaler body located over hinge 760 andthe interior of the inhaler body with the cartridge inlet 719 whichplaces the inhaler in a closed-dosing configuration. A portion of airflow entering the inhaler body through inlet port 710 enters thecartridge inlet 719 and exits through dispensing ports 727 intomouthpiece aperture 755 which then meets bypass air that enters themouthpiece conduit 740 before reaching outlet port 735 and into a user.In this embodiment, the inhaler is configured to have a registrationstructure at predetermined sites to indicate the dosing position and thecontainment position once they are reached during rotational movement ofthe mouthpiece. As with other embodiments herein, a portion of the flowin use diverges and remains circulating in the internal volume of thecontainer to promote entrainment and lifting of a powder medicament inthe container and promote deagglomeration of the powder to form smallmasses of the powder that can exit through the dispensing ports.

Cartridge embodiments for use with the inhalers are describe above, suchas cartridges 150, 170, 780, and 800 illustrated, respectively, in FIGS.4B and 35; FIGS. 15I and 39A; FIG. 40 and FIG. 45. The presentcartridges are configured to contain a dry powder medicament in astorage, tightly sealed or contained position and can be reconfiguredwithin an inhaler from a powder containment position to an inhalation ordosing configuration. In certain embodiments, the cartridge comprises alid or top and a container having one or more apertures, a containmentconfiguration and dosing configuration, an outer surface, an innersurface defining an internal volume; and the containment configurationrestricts communication to the internal volume and the dispensingconfiguration forms an air passage through said internal volume to allowan air flow to enter and exit the internal volume in a predeterminedmanner. For example, the cartridge container can be configured so thatan airflow entering the cartridge air inlet is directed across the airoutlets within the internal volume to meter the medicament leaving thecartridge so that rate of discharge of a powder is controlled; andwherein airflow in the cartridge can tumble substantially perpendicularto the air outlet flow direction, mix and fluidize a powder in theinternal volume prior to exiting through dispensing apertures.

FIG. 35-38B further illustrate cartridge 150 comprising top or lid 156and container 151 defining an interior space or volume. FIG. 36exemplifies the cartridge top 156 having opposing ends and comprisingrecess area 154 and boss 126 at opposing ends of a longitudinal axis X,and relatively rectangular set of panels 152 along the sides and in thelongitudinal axis X, which are integrally configured and attached to top156 at their ends. The border 158 of cartridge top 156 extendsdownwardly and is continuous with panels 152. Panels 152 extenddownwardly from either side of top 156 in the longitudinal axis X andare separated from the area of boss 126 and recess area 154 by alongitudinal space or slit 157. FIGS. 35-37 also show each panel 152further comprising a flange 153 structurally configured to engage withprojections or wings 166 of container 151, support container 151 andallow container 151 to be movable from a containment position underrecess area 154 to a dosing position under area of boss 126. Panels 152are structurally configured with a stop 132 at each end to preventcontainer 151 from moving beyond their end where they are attached toborder 158. In this embodiment, container 151 or lid 156 can be movable,for example, by translational movement upon top 156, or top 156 can bemovable relative to the container 151. In one embodiment, container 151can be movable by sliding on flanges 153 on lid 156 when lid or top 156is stationary, or lid 156 can be movable by sliding on a stationarycontainer 151 depending on the inhaler configuration. Border 158 nearthe boss 126 has a recess area which forms part of the perimeter ofinlet port 119 in the dosing configuration of the cartridge.

FIG. 37 illustrates a bottom view of cartridge 150 showing therelationship of the structures in a containment configuration, such ascontainer 151, dispensing ports 127, panels 152, flanges 153 and areaunder the boss 126 or undersurface 168 which is relatively hollow orrecessed. FIG. 38A illustrates a cross-section through themid-longitudinal axis X of cartridge 150 in a containment configurationand showing container 151 in tight contact with lid 156 at recess area154 and supported by flanges 153. The undersurface of the boss 126 ishollow and can be seen relatively at a higher position than the topborder of container 151. FIG. 38B illustrates cartridge 150 in a dosingconfiguration wherein the upper border of container 151 and panel 158under the area of boss 126 form an inlet port 119 which allows flowentry into the interior of cartridge 151.

In another embodiment, a translational cartridge 170 is illustrated inFIGS. 39A-39I, which is an alternate embodiment of cartridge 150 and canbe used with, for example, inhaler 302 depicted in FIGS. 15C-15L. FIG.39A depicts cartridge 170 comprising an enclosure comprising a top orlid 172 and a container 175 defining an interior space, wherein thecartridge is shown in a containment configuration. In this cartridgeconfiguration, the cartridge top 172 is configured to form a seal withcontainer 175 and container or lid is movable relative to one another.Cartridge 170 can be configured from a containment position (FIGS. 39Aand 39H) to a dosing position (FIGS. 39C-39G and 39I) and to adisposable position (not shown), for example, in the middle of thecartridge, to indicate that the cartridge has been used. FIG. 39A alsoillustrates the various features of cartridge 170, wherein top 172comprises side panels 171 configured to partially cover the exterior ofthe container. Each side panel 172 comprises a flange 177 at its loweredge which forms a track to support wing-like structures of container175, which allows movement of container 175 along the lower border oftop 172. The cartridge top 172 further comprises an exterior relativelyflat surface at one end, a relatively rectangular boss 174 having anopening or dispensing port 173, and a concave or recess area configuredinternally to maintain the contents of container 175 in a tight seal. Inone embodiment, the dispensing port can be configured to have varioussizes, for example, the width and length of the opening can be fromabout 0.025 cm to about 0.25 cm in width and from about 0.125 cm toabout 0.65 cm in length at its entry within the interior of thecartridge. In one embodiment, the dispensing port entry measuresapproximately 0.06 cm in width to 0.3 cm in length. In certainembodiments, cartridge top 172 can comprise various shapes which caninclude grasping surfaces, for example, tabs 176, 179 and otherconfigurations to orient the cartridge in the right orientation forproper placement in the holder, and a securing mechanism, for example, achamfered or beveled edge 180 to adapt securely to a correspondinginhaler. The flanges, external geometry of the boss, tabs, and variousother shapes can constitute keying surfaces that can indicate,facilitate, and/or necessitate proper placement of the cartridge in theinhaler. Additionally, these structures can be varied from oneinhaler-cartridge pairing system to another in order to correlate aparticular medicament or dosage provided by the cartridge with aparticular inhaler. In such manner, a cartridge intended for an inhalerassociated with a first medicament or dosage can be prevented from beingplaced into or operated with a similar inhaler associated with a secondmedicament or dosage.

FIG. 39B is a top view of exemplifying the general shape of a cartridgetop 172 with boss 174, dispensing port 173, recess area 178 and tabs 176and 179. FIG. 39C is a bottom view of cartridge 170 showing container175 in a containment position being supported by its wing-likeprojections 182 by each flange 177 from top 172. FIG. 39D depictscartridge 170 in a dosing configuration further comprising an air inlet181 formed by a notch on the cartridge top 172 and the container 175upper border. In this configuration, air inlet 181 is in communicationwith the interior of the cartridge and forms and air conduit withdispensing port 173. In use, the cartridge air inlet 181 is configuredto direct airflow entering the cartridge interior at the dispensing port173.

FIG. 39F illustrates a side view of cartridge 150, showing therelationship of the structures in a dosing configuration, such ascontainer 175, boss 174, side panels 172, and tab 176. FIG. 39Gillustrates a cartridge 170 in a dosing configuration for use andcomprising a container 175 and a top 172 having a relatively rectangularair inlet 181 and a relatively rectangular dispensing port 173 piercingthrough a boss 174 which is relatively centrally located on thecartridge top 172 upper surface. Boss 174 is configured to fit into anaperture within a wall of a mouthpiece of an inhaler. FIGS. 39H and 39Iillustrate cross-sections through the mid-longitudinal axis X ofcartridge 170 in a containment configuration and dosing configuration,respectively, showing container 175 in contact with the lid 172undersurface of the recess area 178 and supported by flanges 177 whichform tracks for the container to slide from one position to another. Asshown in FIG. 39H, in the containment configuration, container 175 formsa seal with the undersurface of the cartridge top 172 at recess area178. FIG. 39I depicts the cartridge 170 in the dosing configurationwherein the container is at opposing end of the recess area 181 and thecontainer 175 and cartridge top form an air inlet 181 which allowsambient air to enter cartridge 170 as well as to form an air conduitwith dispensing port 173 and the interior of container 175. In thisembodiment, the cartridge top undersurface wherein the dosing positionis attained is relatively flat and container 175 interior surface isconfigured to have somewhat of a U-shape. The boss 174 is configured toslightly protrude above the top surface of cartridge top 172.

In another embodiment of the cartridge, cartridge 780 is described abovewith reference to FIG. 30A and herewith illustrated in FIGS. 40-44.Cartridge 780 can be adapted to the dry powder inhalers disclosedherewith and is particularly suitable for use with an inhaler with arotatable mechanism for moving the inhaler from a containmentconfiguration to a dosing position, wherein the cartridge top is movablerelative to the container, or for moving the container relative to thetop in achieving alignment of the dispensing ports with the container toa dosing position, or moving either the container or the top to thecontainment configuration.

As described above, FIG. 40-44 further illustrate perspective views ofcartridge 780 embodiment for use with, for example, the inhaler of FIG.29, and show a cartridge in a containment configuration comprising acartridge top or lid 756 and container 751 integrally attached to oneanother. Container 751 and top 756 are movable relative to one anotherin a rotating motion from a containment position to a dosing orinhalation position and back. Cartridge top 756 is relatively circularin form and also comprises a recessed area 754 and a raised area or boss726 having dispensing ports 727 and a circular panel 752 extendingdownwardly to enclose and attach to container 751 and defining aninterior space. Top 756 also has a raised top border or top edge 759configured to adapt with an inhaler and a groove in the inside surfaceof panel 752 for engaging with container 751.

FIG. 41 illustrates an exploded view of the cartridge embodiment of FIG.40, showing container 751 defining a chamber 757 for containing amedicament which is continuous with a relatively circular, top portion747 of wider diameter to said chamber and configured to have an engagingmechanism to engage and move relative to cartridge top 756. FIG. 42shows, for example, that upper border 758 of the container can have acircular configuration, for example, a snap ring for engaging withgroove 761 of panel 752 to form cartridge 780. FIG. 42 also illustratesa perspective view of the cartridge embodiment of FIG. 40 incross-section through the perpendicular axis and in the containmentconfiguration, showing recess area 754 sealing container 751 andundersurface 767 of boss 726 being hollow. When recessed area 754 isover container chamber or internal volume 757, the cartridge is in acontainment configuration as illustrated in FIG. 42.

FIG. 43 illustrates a perspective view of a cartridge embodiment of FIG.40 in a dosing configuration, wherein the chamber 757 of container 751is directly under the boss 726 and the cartridge is configured to havean inlet port 719 in communication with dispensing ports 727. FIG. 44illustrates a perspective view of this embodiment in cross-section andin a dosing configuration to show the air inlet 719 and the position ofthe container and boss 726 with dispensing ports 727. In thisembodiment, recess area 754 of lid 756 and area 747 of container form atight abutment or seal on each other.

The air inlet port of a cartridge for use with the present inhalers canbe configured at any point on the cartridge so that a powder medicamentwithin the container can remain in a containment position prior toinhalation. For example, FIGS. 45, 46A, 46B, 47A and 47B illustrate twoalternate embodiments of a cartridge for use with the dry powdersinhaler, comprising a lid or top 856, a container 851 structurallyconfigured as in FIG. 35-39 above. In this embodiment, however, airinlet 819 into the cartridge interior can be incorporated within thecartridge top or lid 851 along with one or more dispensing ports 827. Inthis embodiment, the cartridge comprises a container 851 and a lid ortop 856. Lid or top 856 can be provided with a groove in its interiorsurface to engage with the upper border of the container 851 as lockingmechanism. The cartridge can also be provided with a seal 860 to containa powder medicament within the cartridge and can be made from, forexample, plastic film or laminated foil. Seal 860 can be made to containa single cartridge for single dose use or multiple, single dosecartridges on a strip. Lid 856 contains at least two ports which atleast one works as an air inlet and another as a dispensing port. FIGS.46A and 46B illustrate the embodiment of the cartridge in FIG. 45comprising a container 851 which can be adapted to a lid 856 wherein therelatively square lid has an inlet port 819 relative round and twooutlet ports 827 and a side panel 852 configured to have a groove toadapt to container 851, wherein container 851 is relatively shaped as acup and has a protrusion on his upper border for engaging lid 856. FIG.46B illustrates a perspective view of a cartridge embodiment of FIG. 45in a cross-section and dosing configuration. In this embodiment, thecartridge top air inlet can have various configurations. For example,FIGS. 47A and 47B illustrate and alternate embodiment of cartridge 800,in which the cartridge top 856 is relatively semicircular and flat inshape having an air inlet port rectangular in shape. In this embodiment,the container and cartridge top can be manufactured from a thermoformmaterial, for example, polyethylene pterephthalate, stock to facilitateproduction.

In embodiments described herein, cartridges can be configured to delivera single unit, pre-metered dose of a dry powder medicament. Cartridgessuch as cartridge 150, 170, 780 and 800 can be structurally configuredto contain a dose of, for example, from 0.1 mg to about 50 mg of a drypowder formulation. Thus the size and shape of the container can varydepending on the size of the inhaler and the amount or mass of powdermedicament to be delivered. For example, the container can have arelatively cylindrical shape with two opposing sides relatively flat andhaving an approximate distance between of from about 0.4 cm to about 2.0cm. To optimize the inhaler performance, the height of the inside of thecartridge along the Y axis may vary depending on the amount of powderthat is intended to be contained within the chamber. For example, a fillof 5 mg to 15 mg of powder may optimally require a height of from about0.6 cm to about 1.2 cm.

In an embodiment, a medicament cartridge for a dry powder inhaler isinhaler is provided, comprising: an enclosure configured to hold amedicament; at least one inlet port to allow flow into the enclosure,and at least one dispensing port to allow flow out of the enclosure; theat least one inlet port is configured to direct at least a portion ofthe flow entering the at least one inlet port at the at least onedispensing port within the enclosure in response to a pressuredifferential. In one embodiment, the inhaler cartridge is formed from ahigh density polyethylene plastic. The cartridge has a container whichhas an internal surface defining an internal volume and comprising abottom and side walls contiguous with one another, and having one ormore openings. The can have a cup-like structure and has one openingwith a rim and it is formed by a cartridge top and a container bottomwhich are configurable to define one or more inlet ports and one or moredispensing ports. The cartridge top and container bottom areconfigurable to a containment position, and a dispensing or dosingposition.

In embodiments described herein, the dry powder inhaler and cartridgeform an inhalation system which can be structurally configured toeffectuate a tunable or modular airflow resistance, as it can beeffectuated by varying the cross-sectional area at any section of theairflow conduits of the system. In one embodiment, the dry powderinhaler system can have an airflow resistance value of from about 0.065to about 0.200 (√kPa)/liter per minute. In other embodiments, a checkvalve may be employed to prevent air flow through the inhaler until adesired pressure drop, such as 4 kPa has been achieved, at which pointthe desired resistance reaches a value within the range given herewith.

FIGS. 48-54 illustrate yet another embodiment of the dry powder inhaler.FIG. 48 depicts an inhaler 900 in an open configuration which isstructurally configured similarly as inhaler 300 shown in FIGS. 12-15B.Inhaler 900 comprises mouthpiece 930 and housing subassembly 920 whichare attached to one another by a hinge so that mouthpiece 930 pivotsrelative to the housing subassembly 920. Mouthpiece 930 furthercomprises integrally formed side panels 932 wider than housing 920,which engage with housing protrusions 905 to attain the closedconfiguration of inhaler 900. Mouthpiece 930 further comprises air inlet910, air outlet 935; air flow conduit 940 extending from air inlet 910to air outlet 935 for contacting a user's lips or mouth, and aperture955 on the floor or bottom surface which communicates with airflowconduit 940 of the inhaler. FIG. 49 illustrates inhaler 900 in anexploded view, showing the component parts of the inhaler, including themouthpiece 930 and housing subassembly 920. As depicted in FIG. 49, themouthpiece is configured as a single component and further comprises abar, cylinder or tube 911 configured with teeth or gear 913 forarticulating with housing 920 so that movement of mouthpiece 930relative to housing 920 in an angular direction attains closure of thedevice. An air channel 912 can be provided to the housing which candirect an air flow towards mouthpiece air inlet 910. Air channel 912 isconfigured so that in use, a user's finger placed over the channelcannot limit or obstruct airflow into air conduit 940.

FIG. 48 illustrates the housing subassembly 920 comprising a cartridgeplacement or mounting area 908 and a notch 918 which is configured todefine an air inlet when the inhaler is in a closed configuration. FIG.49 illustrates housing 920 as an enclosure, further comprising twocomponent parts for ease of manufacturing, although less or more partscan be used, including a tray 922, and a cover 925. Tray 922 isconfigured with notches 914 configured near its distal end which housesbar, cylinder or tube 911 in forming a hinge with mouthpiece 930. Tray922 also houses sled 917. Sled 917 is configured to be movable withintray 922 and has a cartridge receiving area 921 and an arm-likestructure having openings 915 for engaging the teeth or gear 913 ofmouthpiece 930 so that in closing the device for use, movement ofmouthpiece 930 relative to housing 920 moves the sled in a proximaldirection, which results in the sled abutting a cartridge containerseated on inhaler holder or mounting area 908 and translocates thecontainer from a containment position to a dosing position. In thisembodiment, a cartridge seated in the cartridge holder 908 has the airinlet opening in a dosing configuration facing towards the proximal endof the inhaler or the user. Housing cover 925 is configured so that itcan securely attach to tray 922 by having, for example, protrusions 926extending from the bottom border as a securing mechanism. FIG. 50illustrates inhaler 900 in the open configuration depicting the positionand orientation of a cartridge 150 in a containment configuration formounting on the inhaler. FIG. 51 further illustrates inhaler 900 in theopen configuration with cartridge 150 seated in the cartridge holder inthe containment configuration. FIG. 52 illustrates a mid-longitudinalsection of the inhaler in FIG. 51 showing the position of the gear 913relative to sled 917 in the containment configuration of the cartridgecontainer 151, which abuts sled 917. In this embodiment, container 151moves relative to cartridge top 156. Upon closing inhaler 900 (FIG. 53)and as mouthpiece 930 moves to attain a closed configuration, sled 917pushes container 151 until the dosing configuration is attained andmouthpiece aperture 955 slides over cartridge boss 126 so thatdispensing ports 127 are in communication with the mouthpiece conduit940 and an air flow pathway is established for dosing through air inletaperture 918, cartridge air inlet 919 and dispensing ports 127 in airconduit 940. As seen in FIG. 54, mouthpiece 930 and therefore, airconduit 940 have a relatively tapered, hour-glass shape configuration atapproximately mid to distal end. In this embodiment, sled 917 isconfigured so that when the inhaler is open after use, the sled cannotreconfigure a cartridge to the containment configuration. In somevariations of this embodiment, it may be possible or desirable toreconfigure the cartridge.

In embodiments disclosed herein, inhaler apertures, for example, 155,255, 355, 955 can be provided with a seal, for example, crushed ribs,conformable surfaces, gaskets, and o-rings to prevent air flow leakageinto the system so that the airflow only travels through the cartridge.In other embodiment, to effectuate the seal, the seal can be provided tothe cartridge. The inhalers are also provided with one or more zones ofdeagglomeration, which are configured to minimize build-up of powder ordeposition. Deagglomeration zones are provided, for example, in thecartridge, including, in the container and the dispensing ports, and atone or more locations in the air conduit of the mouthpiece.

In the embodiments disclosed herein, the dry powder inhaler system isconfigured to have a predetermined flow balance distribution in use,having a first flow pathway through the cartridge and second flowpathway through, for example, the mouthpiece air conduit. FIG. 55 andFIG. 56 depict a schematic representation of air conduits established bythe cartridge and inhaler structural configurations which direct thebalance of flow distribution. FIG. 55 depicts the general direction offlow within a cartridge in the dispensing or dosing position of a drypowder inhaler as shown by the arrows. FIG. 56 illustrates the movementof flow of an embodiment of a dry powder inhaler showing the flowpathways of the inhaler in the dosing position as indicated by thearrows.

The balance of mass flow within an inhaler is approximately 10% to 70%of the volume going through the cartridge flow pathway, and about 30% to90% through the beginning portion of the mouthpiece conduit. In thisembodiment, the airflow distribution through the cartridge mixes themedicament in a tumbling manner to fluidize or aerosolize the dry powdermedicament in the cartridge container. Airflow fluidizing the powderwithin the container then lifts the powder and gradually letting it exitthe cartridge container through the dispensing ports, then shear fromthe airflow entering the mouthpiece conduit converges with the airflowcontaining medicament emanating from the cartridge container.Predetermined or metered exiting airflow from the cartridge convergewith bypass airflow entering the air conduit of the mouthpiece tofurther dilute and deagglomerate the powder medicament prior to exitingthe mouthpiece outlet port and entering the patient.

In yet another embodiment, an inhalation system for delivering a drypowder formulation to a patient is provided, comprising an inhalercomprising a container mounting area configured to receive a container,and a mouthpiece having at least two inlet apertures and at least oneexit aperture; wherein one inlet aperture of the at least two inletapertures is in fluid communication with the container area, and one ofthe at least two inlet apertures is in fluid communication with the atleast one exit aperture via a flow path configured to bypass thecontainer area to deliver the dry powder formulation to the patient;wherein the flow conduit configured to bypass the container areadelivers 30% to 90% of the total flow going through the inhaler duringan inhalation.

In another embodiment, an inhalation system for delivering a dry powderformulation to a patient is also provided, comprising a dry powderinhaler comprising a container region and a container; said dry powderinhaler and container combined are configured to have rigid flowconduits in a dosing configuration and a plurality of structural regionsthat provide a mechanism for powder deagglomeration of the inhalationsystem in use; wherein at least one of the plurality of mechanisms fordeagglomeration is an agglomerate size exclusion aperture in thecontainer region having a smallest dimension between 0.5 mm and 3 mm.

In an alternate embodiment, an inhalation system for delivering a drypowder formulation to a patient is provided, comprising a dry powderinhaler comprising a mouthpiece and a container; said dry powder inhalerand container combined are configured to have rigid flow conduits in adosing configuration and a plurality of structural regions that providea mechanism for powder deagglomeration of the inhalation system in use;wherein at least one of the plurality of mechanisms for deagglomerationis an air conduit configured in the mouthpiece which directs flow at anexit aperture in fluid communication with the container. In particularembodiments, the inhalation system of includes a container furthercomprising a mechanisms for cohesive powder deagglomeration whichcomprises a cup-like structure configured to guide a flow entering thecontainer to rotate, re-circulating in the internal volume of thecup-like structure and lifting up a powder medicament so as to entrainthe powder agglomerates in the flow until the powder mass is smallenough prior to exiting the container. In this embodiment, the cup-likestructure has one or more radii configured to prevent flow stagnation.

In embodiments describe herein, the cartridge is structurally configuredhaving the inlet opening in close proximity to the dispensing ports in ahorizontal and vertical axis. For example, the proximity of the inlet tothe dispensing ports can be immediately next to the air inlet to aboutwithin one cartridge width, although this relationship can varydepending on the flow rate, the physical and chemical properties of thepowder. Because of this proximity, flow from the inlet crosses theopening to the dispensing ports within the cartridge creating a flowconfiguration that inhibits fluidized powder or powder entrained withinthe airflow, from exiting the cartridge. In this manner, during aninhalation maneuver, flow entering the cartridge container caneffectuate tumbling of the dry powder formulation in the cartridgecontainer, and fluidized powder approaching the exit or dispensing portsof a cartridge can be impeded by flow entering the inlet port of thecartridge, thereby, flow within the cartridge can be restricted fromexiting the cartridge container. Due to differences in inertia, density,velocity, charge interaction, position of the flow, only certainparticles can navigate the path needed to exit the dispensing ports.Particles that do not pass through the exit port must continue to tumbleuntil they possess the proper mass, charge, velocity or position. Thismechanism, in effect, can meter the amount of medicament leaving thecartridge and can contribute to deagglomeration of powder. To furtherhelp meter the exiting fluidized powder, the size and number ofdispensing ports can be varied. In one embodiment, two dispensing portsare used, configured to be circular in shape, each 0.10 cm in diameterand positioned near the inlet aperture about middle center line of thecontainer to about 0.2 cm from the centerline towards the air inletport. Other embodiments can, for example, have dispensing ports ofvarious shapes including rectangular wherein the cross-sectional area ofthe one or more dispensing ports ranges from 0.05 cm² to about 0.25 cm².In some embodiments, the sizes ranging of the dispensing ports can befrom about 0.05 cm to about 0.25 cm in diameter. Other shapes andcross-sectional areas can be employed as long as they are similar incross-sectional area to the values given herewith. Alternatively, formore cohesive powders larger cross sectional area of the dispensing portcan be provided. In certain embodiments, the cross sectional area of thedispensing port can be increased depending on the size of theagglomerates relative to the minimum opening dimension of the port orports so that the length relative to the width of the port remainslarge. In one embodiment, the intake aperture is wider in dimension thanthe width of the dispensing port or ports. In embodiments wherein theintake aperture is rectangular, the air inlet aperture comprises a widthranging from about 0.2 cm to about the maximal width of the cartridge.In one embodiment the height is about 0.15 cm, and width of about 0.40cm. In alternate embodiments, the container can have a height of fromabout 0.05 cm to about 0.40 cm. In particular embodiments, the containercan be from about 0.4 cm to about 1.2 cm in width, and from about 0.6 cmto about 1.2 cm in height. In an embodiment, the container comprise oneor more dispensing ports having and each of the ports can have adiameter between 0.012 cm to about 0.25 cm.

In particular inhalation systems, a cartridge for a dry powder inhaler,comprising a cartridge top and a container is provided, wherein thecartridge top configured relatively flat and having one or more openingsand one or more flanges having tracks configured to engage thecontainer; said container having an inner surface defining an internalvolume and is moveably attached to the tracks on the one or more flangeson the cartridge top and configurable to attain a containment positionand a dispensing or dosing position by moving along the tracks of theone or more flanges.

In another embodiment, the inhalation system comprises an enclosurehaving one or more exit ports configured to exclude a powder mass of adry powder composition having a smallest dimension greater than 0.5millimeters and less than 3 mm. In one embodiment, a cartridge for a drypowder inhaler, comprising an enclosure having two or more rigid parts;the cartridge having one or more inlet ports and one or more dispensingports, wherein one or more inlet ports have a total cross-sectional areawhich is larger than the total cross-sectional area of the dispensingports, including wherein the total cross-sectional area of one or moredispensing ports ranges from 0.05 cm² to about 0.25 cm².

In one embodiment, a method for deagglomerating and dispersing a drypowder formulation for inhalation, comprising the steps of: generatingan airflow in a dry powder inhaler comprising a mouthpiece and acontainer having at least one inlet port and at least one dispensingport and containing a dry powder formulation; said container forming anair conduit between the at least one inlet port and the at least onedispensing port and said inlet port directs a portion of the airflowentering said container to the at least one dispensing port; allowingairflow to tumble powder within the container so as to lift and mix thedry powder medicament in the container to form an airflow medicamentmixture; and accelerating the airflow exiting the container through theat least one dispensing port. In this embodiment, the powder medicamentthat passes through the dispensing ports can immediately accelerate dueto reduction in cross-sectional area of the exit ports relative to theinlet port. This change in velocity may further deagglomerate thefluidized and aerosolized powder medicament during inhalation.Additionally, because of the inertia of the particles or groups ofparticles in the fluidized medicament, the velocity of the particlesleaving the dispensing ports is not the same. The faster moving air flowin the mouthpiece conduit imparts a drag or shear force on each particleor group of particles of the slower moving fluidized powder leaving theexit or dispensing port or ports, which can further deagglomerate themedicament.

The powder medicament that passes through the dispensing port or portsimmediately accelerates due to reduction in cross-sectional area of theexit or dispensing ports relative to the container, which are designedto be narrower in cross-sectional area than the air inlet of thecontainer. This change in velocity may further deagglomerate thefluidized powder medicament. Additionally, because of the inertia of theparticles or groups of particles in the fluidized medicament, thevelocity of the particles leaving the dispensing ports and the velocityof the flow passing the dispensing ports is not the same.

In embodiments described herein, powder exiting the dispensing ports canfurther accelerate, for example, by an imparted change in directionand/or velocity of the fluidized medicament. Directional change offluidized powder leaving the dispensing port and entering the mouthpiececonduit can occur at an angle of approximately 0° to about 180°, forexample approximately 90°, to the axis of the dispensing port. Change inflow velocity and direction may further deagglomerate the fluidizedpowder through the air conduits. The change in direction can beaccomplished through geometric configuration changes of the air flowconduit and/or by impeding the air flow exiting the dispensing portswith a secondary air flow entering the mouthpiece inlet. The fluidizedpowder in the mouthpiece conduit expands and decelerates as it entersthe oral placement portion of the mouthpiece prior to exiting due to across-sectional area increase in the conduit. Gas trapped withinagglomerates also expands and may help to break apart the individualparticles. This is a further deagglomeration mechanism of theembodiments described herein. Airflow containing medicament can enterthe patient's oral cavity and be delivered effectively, for example,into the pulmonary circulation.

Each of the deagglomeration mechanisms described herein and part of theinhalation system represent a multi-stage approach which maximizespowder deagglomeration. Maximal deagglomeration and delivery of powdercan be obtained by optimizing the effect of each individual mechanism,including, one or more acceleration/deceleration conduits, drag, orexpansion of gas trapped within the agglomerates, interactions of powderproperties with those of the inhaler components material properties,which are integral characteristics of the present inhaler system. In theembodiments described herein, the inhalers are provided with relativelyrigid air conduits or plumbing system to maximize deagglomeration ofpowder medicament so that there is consistency of the powder medicamentdischarge from the inhaler during repeated use. Since the presentinhalers are provided with conduits which are rigid or remain the sameand cannot be altered, variations in the air conduit architectureresulting from puncturing films or peeling films associated with priorart inhalers using blister packs are avoided.

In one embodiment, there is provided a method of deagglomerating apowder formulation in a dry powder inhalation system, comprising:providing the dry powder formulation in a container having an internalvolume to a dry powder inhaler; allowing a flow to enter said containerwhich is configured to direct a flow to lift, entrain and circulate thedry powder formulation until the powder formulation comprises powdermasses sufficiently small to pass through one or more dispensingapertures into a mouthpiece. In this embodiment, the method can furthercomprise the step of accelerating the powder masses entrained in theflow leaving the one or more dispensing apertures and entering themouthpiece.

In embodiments disclosed herein, a dry powder medicament is dispensedwith consistency from the inhaler in less than about 2 seconds. Thepresent inhaler system has a high resistance value of approximately0.065 to about 0.20 (√kPa)/liter per minute. Therefore, in the systemcomprising a cartridge, peak inhalation pressure drops applied ofbetween 2 and 20 kPa produce resultant peak flow rates of about throughthe system of between 7 and 70 liters per minute. These flow ratesresult in greater than 75% of the cartridge contents dispensed in fillmasses between 1 and 30 mg of powder. In some embodiments, theseperformance characteristics are achieved by end users within a singleinhalation maneuver to produce cartridge dispense percentage of greaterthan 90%. In certain embodiments, the inhaler and cartridge system areconfigured to provide a single dose by discharging powder from theinhaler as a continuous flow, or as one or more pulses of powderdelivered to a patient. In an embodiment, an inhalation system fordelivering a dry powder formulation to a patient's lung is provided,comprising a dry powder inhaler configured to have flow conduits with atotal resistance to flow in a dosing configuration ranging in value from0.065 to about 0.200 (√kPa)/liter per minute. In this and otherembodiments, the total resistance to flow of the inhalation system isrelatively constant across a pressure differential range of between 0.5kPa and 7 kPa.

The structural configuration of the inhaler allows the deagglomerationmechanism to produce respirable fractions greater than 50% and particlesof less than 5.8 μm. The inhalers can discharge greater than 85% of apowder medicament contained within a container during an inhalationmaneuver. Generally, the inhalers herein depicted in FIG. 15I candischarge greater that 90% of the cartridge contents or containercontents in less than 3 seconds at pressure differentials between 2 and5 kPa with fill masses ranging up to 30 mg.

While the present inhalers are primarily described as breath-powered, insome embodiments, the inhaler can be provided with a source forgenerating the pressure differential required to deagglomerate anddeliver a dry powder formulation. For example, an inhaler can be adaptedto a gas powered source, such as compressed gas stored energy source,such as from a nitrogen can, which can be provided at the air inletports. A spacer can be provided to capture the plume so that the patientcan inhale at a comfortable pace.

In embodiments described herewith, the inhaler can be provided as areusable inhaler or as a single use inhaler. In alternate embodiments, asimilar principle of deagglomeration can be adapted to multidoseinhalers, wherein the inhaler can comprise a plurality of, for example,cartridge like structures in a single tray and a single dose can bedialed as needed. In variations of this embodiment, the multidoseinhaler can be provided with enough doses for example for a day, a weekor a month supply of a medication. In the multidose embodimentsdescribed herein, end-user convenience is optimized. For example, inprandial regimens breakfast, lunch and dinner dosing is achieved for acourse of 7 days in a single device. Additional end-user convenience isprovided by an indicator mechanism that indicates the day and dosing,for example, day 3 (D3), lunchtime (L). An exemplary embodiment isillustrated in FIGS. 57-68, wherein the inhaler 950 comprises arelatively circular shape comprising a plurality of dosing units as partof a disk-like cartridge system. Inhaler 950 comprises a mouthpiece 952having air inlet 953 and air outlet 954 and housing subassembly 960.Mouthpiece 952 is configured to have a relatively hour glass shape andtherefore air conduit 980 (FIG. 67) is configured with a correspondingshape. Mouthpiece 952 also comprises a cover for engaging with housingsubassembly 960 and an air conduit 980 having an opening 985 (FIG. 67)which communicates with the interior of housing subassembly 960.

FIG. 58 is an exploded view of the inhaler of FIG. 57 showing thecomponent parts, including mouthpiece 952; housing subassembly 960comprising multiple parts, including bottom cover or tray 955, anactuator 956 having a ratchet 957, a cartridge disk system with a bottomtray portion 958 and a lid portion 959 and a seal disk or plate 961. Inone embodiment, a spring can be provided with ratchet 957 to index tray958. Housing tray 955 is structurally configured so that it can engagesecurely with the mouthpiece, for example, snap fits, ultrasonic weld,threads and the like. FIG. 59 illustrates the bottom tray portion 958 ofthe cartridge disk system showing an outer gear mechanism 963 and aninner gear mechanism 964 with relative position around the center axisof the cartridge disk. The cartridge system is configured to have acentrally located aperture for engaging with the actuator. FIG. 59 alsoshows the position of the plurality of unit dose containers 962, eachconfigured of the same dimension and shape and are radially locatedtowards the periphery of the cartridge disk system. FIG. 60 illustratesthe housing tray showing the actuator 956 and the ratchet system 957,957′ in place without a return spring. FIG. 61 depicts the bottomportion 958 of the cartridge disk system showing the plurality ofcontainers 962 radially located within the disk and also showing arelatively circular raised area 965 comprising two projections 966 placein the horizontal plane of the disk and a second projection 967 locatedin the central axis and projecting upwards and perpendicular to thedisk. FIG. 62 illustrates housing tray 955 with the cartridge disksystem 958, 959, actuator 956, and ratchet system assembled therein.

FIG. 63 depicts the cartridge disk system of inhaler 950 in an assembledconfiguration showing the plurality of containers 962 and can engageablyattach to one another to provide powder containment. The cartridgesystem lid portion 959 comprises a plurality of cartridge-like tops 970which in alignment correspond to the containers 962 of the bottom trayof the cartridge disk system to form a plurality of unit dose cartridgeunits within the cartridge disk system. Alignment of the cartridgesystem lid 959 and bottom tray portion is achieved by the lid portion959 having a centrally located aperture 969 configured with two notches968 which engage securely with the raised area of the bottom trayportion 958. In this embodiment, the cartridge disk system is alsoconfigured to have a plurality of air inlets 971 and a plurality ofdispensing ports 972, wherein each unit dose cartridge comprises atleast one air inlet 971 and one ore more dispensing ports 972. FIG. 64shows a cross-section of a cartridge disk system 958, 959 showing airinlet 971 establishing an air conduit pathway in the interiorcompartment of the container with the dispensing ports 972 so that anairflow entering the unit compartment enters through air inlet 971,tumbles inside the container and exits through the dispensing ports.

FIG. 65 illustrates the housing subassembly 960 assembled with itscomponent parts, in particular, the seal disk 961 is illustratedcomprising an aperture 977 located toward the edge of the disk whichaligns with the dispensing ports 972 of a unit dose cartridge of thecartridge disk system in the dosing position. Seal disk 961 is alsoconfigured to seal dispensing ports 972 and air inlets 971 into the unitdose cartridge of the cartridge disk system, except for the unit dosecartridge that is in alignment with aperture 977. In this manner, powdercontainment in a filled cartridge system is maintained. Seal disk 961also has a central opening 975 and a plurality of spring-likestructures, exemplified as undulating elements, or arms 973 extendingfrom the disk inner portion with reference to the central axis, whichform a plurality of openings 976 that allow air flow into the interiorof the inhaler 950 and into the unit dose cartridge being dispensed whenin use. FIG. 66 is a cross-section of the housing subassembly 960showing seal disk 961 configuration which restricts air passage into theunit dose cartridge of all cartridge units except at aperture 977 of theseal disk cartridge disk system. FIG. 67 shows inhaler 950 incross-section showing the dosing configuration, wherein the mouthpieceshows air conduit 980 and mouthpiece aperture 985 aligned with thedispensing ports 972 of a unit dose cartridge and aperture 977 of theseal disk. The other units in the cartridge are in containment by sealdisk 961.

In this embodiment, the inhaler device 950 is simple to use and can beused one cartridge at a time and for dosing. After all dosages aredispensed the inhaler can be disposed or reloaded with a new cartridgedisk system. In this embodiment, movement from an initial position to anadjacent cartridge is effectuated by actuator 956 through acomplementary ratchet system 957. One ratchet which is attached to theactuator advances the cartridge disk, while another holds the cartridgedisk in place while the actuator resets to its original position.

FIGS. 68 through 79 illustrate an alternate embodiment of a multidoseinhaler 990 comprising a mouthpiece 952 and an inhaler body 991.Mouthpiece 952 having an air inlet port 953, an air outlet port 954 andconfigured to have a relatively hour glass shape having an aperture forcommunicating with the body 991 and attached to inhaler body 991. FIGS.69-73 disclosed the various component parts of inhaler 990. In thisembodiment, inhaler body 991 comprises several parts with the cartridgedisk system forming the bottom portion of the body 991. FIG. 74 shows agear drive assembly comprising first gear 992 and second gear 993 isused to rotate a unit dose cartridge to alignment with the mouthpieceaperture for dispensing. An alphanumeric indicator system can be appliedto the cartridge container to indicate the dose unit being dispensed.FIG. 75 shows the cartridge unit system comprising bottom tray portion958 comprising a plurality of wells or unit dose containers 962 radiallylocated and a plurality of air inlet ports, and a lid or top portion 959comprising a cartridge cover plate that can be glued or weldedpermanently on the bottom disk containing the wells. FIG. 76 shows aback view of the cartridge disk system and FIG. 77 shows a front view ofthe cartridge disk comprising a plurality of cartridge tops which can bemovable in the cartridge from a containment position to a dosingposition. FIG. 78 shows a bottom view of the cartridge system of theinhaler 990 showing the position numerically, represented by at leastone numeral 994 of the order in which the doses are dispensed. FIG. 79shows a disk seal having an aperture to align with the dispensing portsof a unit dose cartridge of the cartridge disk system.

In one embodiment, the dry powder medicament may comprise, for example,a diketopiperazine and a pharmaceutically active ingredient. In thisembodiment, the pharmaceutically active ingredient or active agent canbe any type depending on the disease or condition to be treated. Inanother embodiment, the diketopiperazine can include, for example,symmetrical molecules and asymmetrical diketopiperazines having utilityto form particles, microparticles and the like, which can be used ascarrier systems for the delivery of active agents to a target site inthe body. The term ‘active agent’ is referred to herein as thetherapeutic agent, or molecule such as protein or peptide or biologicalmolecule, to be encapsulated, associated, joined, complexed or entrappedwithin or adsorbed onto the diketopiperazine formulation. Any form of anactive agent can be combined with a diketopiperazine. The drug deliverysystem can be used to deliver biologically active agents havingtherapeutic, prophylactic or diagnostic activities.

One class of drug delivery agents that has been used to producemicroparticles that overcome problems in the pharmaceutical arts such asdrug instability and/or poor absorption, are the 2,5-diketopiperazines.2,5-diketopiperazines are represented by the compound of the generalFormula 1 as shown below where E=N. One or both of the nitrogens can bereplaced with oxygen to create the substitution analogs diketomorpholineand diketodioxane, respectively.

These 2,5 diketopiperazines have been shown to be useful in drugdelivery, particularly those bearing acidic R groups (see for exampleU.S. Pat. No. 5,352,461 entitled “Self Assembling Diketopiperazine DrugDelivery System;” U.S. Pat. No. 5,503,852 entitled “Method For MakingSelf-Assembling Diketopiperazine Drug Delivery System;” U.S. Pat. No.6,071,497 entitled “Microparticles For Lung Delivery ComprisingDiketopiperazine;” and U.S. Pat. No. 6,331,318 entitled“Carbon-Substituted Diketopiperazine Delivery System,” each of which isincorporated herein by reference in its entirety for all that it teachesregarding diketopiperazines and diketopiperazine-mediated drugdelivery). Diketopiperazines can be formed into drug adsorbingmicroparticles. This combination of a drug and a diketopiperazine canimpart improved drug stability and/or absorption characteristics. Thesemicroparticles can be administered by various routes of administration.As dry powders these microparticles can be delivered by inhalation tospecific areas of the respiratory system, including the lungs.

Methods for synthesizing diketopiperazines are described in, forexample, Katchalski, et al., J. Amer. Chem. Soc. 68, 879-880 (1946) andKopple, et al., J. Org. Chem. 33(2), 862-864 (1968), the teachings ofwhich are incorporated herein by reference in their entirety.2,5-diketo-3,6-di(aminobutyl)piperazine (Katchalski et al. refer to thisas lysine anhydride) can also be prepared via cyclodimerization ofN-ε-P-L-lysine in molten phenol, similar to the Kopple method, followedby removal of the blocking (P)-groups with 4.3 M HBr in acetic acid.This route can be preferred because it uses a commercially availablestarting material, it involves reaction conditions that are reported topreserve stereochemistry of the starting materials in the product andall steps can be easily scaled up for manufacture. Methods forsynthesizing diketopiperazines are also described in U.S. PatentPublication No. 2006/004133 entitled, “Catalysis of DiketopiperazineSynthesis,” which is also incorporated by reference herein for itsteachings regarding the same.

The fumaryl diketopiperazine(bis-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP) is onepreferred diketopiperazine for pulmonary applications:

FDKP provides a beneficial microparticle matrix because it has lowsolubility in acid but is readily soluble at neutral or basic pH. Theseproperties allow FDKP to crystallize under acidic conditions and thecrystals self-assemble to form particles. The particles dissolve readilyunder physiological conditions where the pH is neutral. As noted,microparticles having a diameter of between about 0.5 and about 10microns can reach the lungs, successfully passing most of the naturalbarriers. Particles in this size range can be readily prepared fromFDKP. In one embodiment, the microparticles disclosed herein are FDKPmicroparticles loaded with an active agent such as insulin.

FDKP is a chiral molecule having trans and cis isomers with respect tothe arrangement of the substituents on the substituted carbons on theDKP ring. As described in U.S. Provisional Patent Application No.61/186,779 entitled DIKETOPIPERAZINE MICROPARTICLES WITH DEFINED ISOMERCONTENTS filed on date even with the present disclosure, more robustaerodynamic performance and consistency of particle morphology can beobtained by confining the isomer content to about 45-65% trans. Isomerratio can be controlled in the synthesis and recrystallization of themolecule. Exposure to base promotes ring epimerization leading toracemization, for example during the removal of protecting groups fromthe terminal carboxylate groups. However increasing methanol content ofthe solvent in this step leads to increased trans isomer content. Thetrans isomer is less soluble than the cis isomers and control oftemperature and solvent composition during recrystallization can be usedto promote or reduce enrichment for the trans isomer in this step.

FDKP possesses two asymmetric centers in the diketopiperazine ring. FDKPis manufactured as a mixture of geometric isomers that are identified as“cis-FDKP” and “trans-FDKP” according to the arrangement of side chainsrelative to the central “ring” of the diketopiperazine. The R,R and S,Senantiomers have the propenyl(amidobutyl) “side arms” projecting fromthe same planar side of the diketopiperazine ring (A and B below) andare thus referred to as the cis isomers while the R,S compound has the“side arms” projecting from opposite planar sides of thediketopiperazine ring (C below) and is referred to as the trans isomer.

FDKP microparticle powders with acceptable aerodynamic performance, asmeasured by RF/fill with moderately efficient inhalers such as theMEDTONE® inhaler disclosed in U.S. Pat. No. 7,464,706 entitled, “UnitDose Cartridge and Dry Powder Inhaler,” which is incorporated byreference herein for its teachings regarding the same, have beenproduced from FDKP with a trans isomer content ranging from about 45 toabout 65%. Particles with isomer content in this range also perform wellwith high efficiency inhalers such as that disclosed in U.S. patentapplication Ser. No. 12/484,137 entitled, “A Dry Powder Inhaler andSystem for Drug Delivery,” filed on Jun. 12, 2009, which is incorporatedby reference herein for its teachings regarding the same. Microparticlepowders containing more than 65% trans-FDKP tend to have lower and morevariable RF/fill (FIG. 82). Trans-enriched particles have alteredmorphology and also lead to viscous suspensions which are difficult toprocess.

In other experiments done under comparable conditions to those reportedin FIG. 82, microparticles made from about 95% trans-enriched FDKP andloaded with insulin gave an RF/fill of about 24% whereas control sampleswith a trans isomer content of about 59% gave an RF/fill of about 49-52%(data not shown). Accordingly, a microparticle powder having a transisomer content of about 45 to about 65% provides a powder withacceptable aerodynamic properties. In alternate embodiments the transisomer content ranges from about 53 to about 65% (see FIG. 82) or fromabout 53 to about 63%, or from about 50 to about 56%, or from about 54to about 56%.

Based on the foregoing, it is desirable to produce microparticle powdershaving a trans isomer content within the range of about 45 to about 65%.That isomer content would affect the aerodynamic performance of FDKPmicroparticles was not anticipated. However, it was discovered thatimproved consistency could be obtained by carefully controlling theisomer content of the FDKP used to make the microparticles. In FIG. 82,the solid curved line represents predicted RF/fill and the dashed curvedline represents the one-sided lower 95% confidence limit of obtaining anappropriate RF/fill score. The vertical dashed lines provide limits onthe trans isomer content for one exemplary embodiment disclosed herein.

The FDKP cis/trans isomer ratio is established during the manufacturingsteps depicted in FIG. 83.

Control of the Lower End of the Trans Isomer Content

The lower end of the trans isomer content is controlled by exposing theDKP ring to a strong base. In one manufacturing step, ethyl protectinggroups are removed by saponification with sodium hydroxide. These basicconditions promote ring epimerization between isomers as shown below,without regard for which isomer is in excess. Thus, the addition of baseto material with 95% trans isomer appeared to favor an approximate 50/50mixture of cis and trans isomers (FIG. 84). Other factors, such asconcentration of co-solvents like methanol, may also affect isomercontent.

Control of the Upper End of the Trans Isomer Range

Differences in solubility between the isomers affect the FDKP isomercontent. For instance, FDKP can be recrystallized from trifluoroaceticacid (TFA) and glacial acetic acid (GAA). Trans FDKP is less soluble inthis solvent system than cis FDKP. Accordingly, conditions that favorselective precipitation of the less soluble trans isomer can be used toincrease the trans isomer content of the final product. Such conditionsinclude decreased recrystallization time, anti-solvent addition at lowtemperature and/or rapid cooling of the TFA-GAA mixture (FIG. 85). Itwill also be appreciated that elevating the trans isomer content by suchmethods provides a residual solution of FDKP enriched in the cisisomers.

TABLE 1 Exemplary Manufacturing Ranges Parameter Suggested OperatingRange TFA/GAA Ratio 0.67 ± 0.05 Crystallization Time (hrs)   6 ± 0.5Crystallization Temp (° C.) 15-25 Cooling Ramp Post GAA Addition (°C./hr)  7-10

Providing microparticles with an isomer content in the about 45 to about65% range provides microparticles with beneficial aerodynamiccharacteristics.

As long as the microparticles described herein retain the requiredisomer content, they can adopt other additional characteristicsbeneficial for delivery to the lung and/or drug adsorption. U.S. Pat.No. 6,428,771 entitled “Method for Drug Delivery to the PulmonarySystem” describes DKP particle delivery to the lung and is incorporatedby reference herein for its teachings regarding the same. U.S. Pat. No.6,444,226, entitled, “Purification and Stabilization of Peptide andProtein Pharmaceutical Agents” describes beneficial methods foradsorbing drugs onto microparticle surfaces and is also incorporated byreference herein for its teachings regarding the same. Microparticlesurface properties can be manipulated to achieve desired characteristicsas described in U.S. patent application Ser. No. 11/532,063 entitled“Method of Drug Formulation based on Increasing the Affinity ofCrystalline Microparticle Surfaces for Active Agents” which isincorporated by reference herein for its teachings regarding the same.U.S. patent application Ser. No. 11/532,065 entitled “Method of DrugFormation based on Increasing the Affinity of Active Agents forCrystalline Microparticle Surfaces” describes methods for promotingadsorption of active agents onto microparticles. U.S. patent applicationSer. No. 11/532,065 is also incorporated by reference herein for itsteachings regarding the same.

Selection and Incorporation of Active Agents

The microparticles described herein can be loaded with one or moreactive agents. As used herein “active agent”, used interchangeably with“drug” refers to pharmaceutical substances, small moleculepharmaceuticals, biologicals and bioactive agents. Active agents can benaturally occurring, recombinant or synthetic proteins, polypeptides,peptides, nucleic acids, organic macromolecules, synthetic organiccompounds, polysaccharides and other sugars, fatty acids, and lipids,and antibodies and fragments thereof, including, but not limited to,humanized or chimeric antibodies, F(ab), F(ab)₂, a single-chain antibodyalone or fused to other polypeptides or therapeutic or diagnosticmonoclonal antibodies to cancer antigens. The active agents can fallunder a variety of biological activity classes, such as vasoactiveagents, neuroactive agents, hormones, anticoagulants, immunomodulatingagents, cytotoxic agents, antibiotics, antiviral agents, antigens,infectious agents, inflammatory mediators, hormones, and cell surfaceantigens. More particularly, active agents can include, in anon-limiting manner, cytokines, lipokines, enkephalins, alkynes,cyclosporins, anti-IL-8 antibodies, IL-8 antagonists including ABX-IL-8;prostaglandins including PG-12, LTB receptor blockers including LY29311,BIIL 284 and CP105696; triptans such as sumatriptan and palmitoleate,insulin and analogs thereof, growth hormone, parathyroid hormone (PTH),parathyroid hormone related peptide (PTHrP), ghrelin, granulocytemacrophage colony stimulating factor (GM-CSF), amylin, amylin analogs,glucagon-like peptide 1 (GLP-1), Texas Red, clopidogrel, PPACK(D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), oxyntomodulin(OXN), peptide YY(3-36) (PYY), adiponectin, cholecystokinin (CCK),secretin, gastrin, glucagon, motilin, somatostatin, brain natriureticpeptide (BNP), atrial natriuretic peptide (ANP), IGF-1, growth hormonereleasing factor (GHRF), integrin beta-4 precursor (ITB4) receptorantagonist, nociceptin, nocistatin, orphanin FQ2, calcitonin, CGRP,angiotensin, substance P, neurokinin A, pancreatic polypeptide,neuropeptide Y, delta-sleep-inducing peptide and vasoactive intestinalpeptide.

The range of loading of the drug to be delivered is typically betweenabout 0.01% and about 20%, depending on the form and size of the drug tobe delivered. For insulin, preferred loads are about 10-15%(corresponding to 3-4 U/mg).

The following describes a manufacturing process that can be used toproduce insulin-loaded FDKP microparticles with a trans isomer contentfrom about 45 to about 65%.

Insulin-loaded FDKP microparticles can be prepared according to theschematic depicted in FIG. 5. Using a Dual-feed Sonolator™, equal massesof about 10.5 wt % acetic acid and about 2.5 wt % FDKP solutions atabout 16° C.±about 2° C. (Table 2 and 3) can be fed at 2000 psi througha 0.001-in² orifice. The precipitate can be collected in a DI waterreservoir of about equal mass and temperature. At this point thesuspension contains about 0.8% solids. The precipitate can beconcentrated and washed by tangential flow filtration. The precipitatecan be first concentrated to about 4% solids then washed with DI water.The suspension can be finally concentrated to about 10% solids based onthe initial mass of FDKP. The concentrated suspension can be assayed forsolids content by an oven drying method.

A concentrated insulin stock solution can be prepared with 1 partinsulin and 9 parts about 2% wt acetic acid. The insulin stock can beadded gravimetrically to the suspension to obtain a load of about 11.4%wt. The insulin-loaded suspension can be mixed at least about 15minutes, and then titrated with about 14 to about 15 wt % aqueousammonia to a pH of about 4.5 from an initial pH of about 3.5. Thesuspension can be flash frozen in liquid nitrogen to form pellets andlyophilized to yield the bulk insulin-loaded FDKP microparticles with a% trans isomer content of between about 45% and 65%. Blank FDKPmicroparticles can be manufactured identically minus the insulin loadingand pH adjustment steps.

TABLE 2 10.5% Acetic Acid Solution Component wt % DI Water 89.00 GAA10.50 10% Polysorbate 80 0.50 0.2 μm filtered

TABLE 3 2.5% FDKP Solution Component wt % DI Water 95.40 FDKP 2.50 NH₄OH1.60 10% Polysorbate 80 0.50 0.2 μm filtered

As used herein, “solvent” refers to the fluid medium in which the activeagent and microparticle are “bathed.” It should not be interpreted torequire that all components are in solution. Indeed in many instances itmay be used to refer to the liquid medium in which the microparticlesare suspended.

As is evident from the foregoing disclosure, microparticles ofembodiments disclosed herein can take many different forms andincorporate many different drugs or active agents. The common attributeof each of these embodiments, however, is that the formed microparticleshave a trans isomer content of about 45 to about 65%.

Microparticles having a diameter of between about 0.5 and about 10microns can reach the lungs, successfully passing most of the naturalbarriers. A diameter of less than about 10 microns is required tonavigate the turn of the throat and a diameter of about 0.5 microns orgreater is required to avoid being exhaled. DKP microparticles with aspecific surface area (SSA) of between about 35 and about 67 m2/gexhibit characteristics beneficial to delivery of drugs to the lungssuch as improved aerodynamic performance and improved drug adsorption.

As described in U.S. Provisional Patent Application No. 61/186,773entitled DIKETOPIPERAZINE MICROPARTICLES WITH DEFINED SPECIFIC SURFACEAREAS filed on date even with the present disclosure, the sizedistribution and shape of FDKP crystals are affected by the balancebetween the nucleation of new crystals and the growth of existingcrystals. Both phenomena depend strongly on concentrations andsupersaturation in solution. The characteristic size of the FDKP crystalis an indication of the relative rates of nucleation and growth. Whennucleation dominates, many crystals are formed but they are relativelysmall because they all compete for the FDKP in solution. When growthdominates, there are fewer competing crystals and the characteristicsize of the crystals is larger.

Crystallization depends strongly on supersaturation which, in turn,depends strongly on the concentration of the components in the feedstreams. Higher supersaturation is associated with the formation of manysmall crystals; lower supersaturation produces fewer, larger crystals.In terms of supersaturation: 1) increasing the FDKP concentration raisesthe supersaturation; 2) increasing the concentration of ammonia shiftsthe system to higher pH, raises the equilibrium solubility and decreasesthe supersaturation; and 3) increasing the acetic acid concentrationincreases the supersaturation by shifting the endpoint to lower pH wherethe equilibrium solubility is lower. Decreasing the concentrations ofthese components induces the opposite effects.

Temperature affects FDKP microparticle formation through its effect onFDKP solubility and the kinetics of FDKP crystal nucleation and growth.At low temperatures, small crystals are formed with high SSA.Suspensions of these particles exhibit high viscosity indicating stronginter-particle attractions. A temperature range of about 12 to about 26°C. produced particles with acceptable (or better) aerodynamicperformance with various inhaler systems including inhaler systemsdisclosed herein.

These present devices and systems are useful in the pulmonary deliveryor powders with a wide range of characteristics. Embodiments of theinvention include systems comprising an inhaler, an integral orinstallable unit dose cartridge, and powder of defined characteristic(s)providing an improved or optimal range of performance. For example, thedevices constitute an efficient deagglomeration engine and thus caneffectively deliver cohesive powders. This is distinct from the coursepursued by many others who have sought to develop dry powder inhalationsystems based on free flowing or flow optimized particles (see forexample U.S. Pat. Nos. 5,997,848 and 7,399,528, US Patent ApplicationNo. 2006/0260777; and Ferrari et al. AAPS PharmSciTech 2004; 5 (4)Article 60). Thus embodiments of the invention include systems of thedevice plus a cohesive powder.

Cohesiveness of a powder can be assessed according to its flowability orcorrelated with assessments of shape and irregularity such as rugosity.As discussed in the US Pharmacopeia USP 29, 2006 section 1174 fourtechniques commonly used in the pharmaceutical arts to assess powderflowability: angle of repose; compressibility (Carr's) index and Hausnerratio; flow through an orifice; and shear cell methods. For the lattertwo no general scales have been developed due to diversity ofmethodology. Flow through an orifice can be used to measure flow rate oralternatively to determine a critical diameter that allows flow.Pertinent variables are the shape and diameter of the orifice, thediameter and height of the powder bed, and the material the apparatus ismade of. Shear cell devices include cylindrical, annular, and planarvarieties and offer great degree of experimental control. For either ofthese two methods description of the equipment and methodology arecrucial, but despite the lack of general scales they are successfullyused to provide qualitative and relative characterizations of powderflowability.

Angle of repose is determined as the angle assumed by a cone-like pileof the material relative to a horizontal base upon which it has beenpoured. Hausner ratio is the unsettled volume divided by the tappedvolume (that is the volume after tapping produces no further change involume), or alternatively the tapped density divided by the bulkdensity. The compressibility index (CI) can be calculated from theHausner ratio (HR) asCI=100×(1−(1/HR)).

Despite some variation in experimental methods generally accepted scalesof flow properties have been published for angle of repose,compressibility index and Hausner ratio (Carr, R L, Chem. Eng. 1965,72:163-168).

Flow Angle of Hausner Compressibility Character Repose Ratio Index (%)Excellent 25-30° 1.00-1.11 ≦10 Good 31-35° 1.12-1.18 11-15 Fair 36-40°1.19-1.25 16-20 Passable 41-45° 1.26-1.34 21-25 Poor 46-55° 1.35-1.4526-31 Very Poor 56-65° 1.46-1.59 32-27 Very, Very ≧66° ≧1.60 ≧38 Poor

The CEMA code provides a somewhat different characterization of angle ofrepose.

Angle of repose Flowability ≦19° Very free flowing 20-29° Free flowing30-39° Average ≧40° Sluggish

Powders with a flow character according to the table above that isexcellent or good can be characterized in terms of cohesiveness as non-or minimally cohesive, and the powders with less flowability as cohesiveand further dividing them between moderately cohesive (corresponding tofair or passable flow character) and highly cohesive (corresponding toany degree of poor flow character). In assessing angle of repose by theCEMA scale powders with an angle of repose ≧30° can be consideredcohesive and those ≧40° highly cohesive. Powders in each of theseranges, or combinations thereof, constitute aspects of distinctembodiments of the invention.

Cohesiveness can also be correlated with rugosity, a measure of theirregularity of the particle surface. The rugosity is the ratio of theactual specific surface area of the particle to that for an equivalentsphere:

${Rugosity} = \frac{({SSA})_{particle}}{({SSA})_{sphere}}$

Methods for direct measurement of rugosity, such as air permeametry, arealso known in the art. Rugosity of 2 or greater has been associated withincreased cohesiveness. It should be kept in mind that particle sizealso affects flowability so that larger particles (for example on theorder of 100 microns) can have reasonable flowability despite somewhatelevated rugosity. However for particles useful for delivery into thedeep lung, such as those with primary particle diameters of 1-3 microns,even modestly elevated rugosity or 2-6 may be cohesive. Highly cohesivepowders can have rugosities ≧10 (see example A below).

Many of the examples below involve the use of dry powders comprisingfumaryl diketopiperazine(bis-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; FDKP). Thecomponent microparticles are self-assembled aggregates of crystallineplates. Powders comprised of particles with plate-like surfaces areknown to have generally poor flowability, that is, they are cohesive.Indeed smooth spherical particles generally have the best flowability,with flowability generally decreasing as the particles become oblong,have sharp edges, become substantially two dimensional and irregularlyshaped, have irregular interlocking shapes, or are fibrous. While notwanting to be bound, it is the applicants' present understanding thatthe crystalline plates of the FDKP microparticles can interleave andinterlock contributing to the cohesiveness (the inverse of flowability)of bulk powders comprising them and additionally making the powder moredifficult to deagglomerate than less cohesive powders. Moreover factorsaffecting the structure of the particles can have effects on aerodynamicperformance. It has been observed that as specific surface area of theparticles increases past a threshold value their aerodynamicperformance, measured as respirable fraction, tends to decrease.Additionally FDKP has two chiral carbon atoms in the piperazine ring, sothat the N-fumaryl-4-aminobutyl arms can be in cis or transconfigurations with respect to the plane of the ring. It has beenobserved that as the trans-cis ratio of the FDKP used in making themicroparticles departs from an optimal range including the racemicmixture respirable fraction is decreased and at greater departures fromthe preferred range the morphology of the particles in SEM becomesvisibly different. Thus embodiments of the invention include systems ofthe device plus DKP powders with specific surface areas within preferredranges, and the device plus FDKP powders with trans-cis isomer ratioswithin preferred ranges.

FDKP microparticles either unmodified or loaded with a drug, for exampleinsulin, constitute highly cohesive powders. FDKP microparticles havebeen measured to have a Hausner ratio of 1.8, a compressibility index of47%, and an angle of repose of 40°. Insulin loaded FDKP microparticles(TECHNOSPHERE® INSULIN; TI) have been measured to have a Hausner ratioof 1.57, a compressibility index of 36%, and an angle of repose of50°±3°. Additionally in critical orifice testing it was estimated thatto establish flow under gravity an orifice diameter on the order of 2 to3 feet (60-90 cm) would be needed (assumes a bed height of 2.5 feet;increased pressure increased the size of the diameter needed). Undersimilar conditions a free flowing powder would require an orificediameter on the order of only 1-2 cm (Taylor, M. K. et al. AAPSPharmSciTech 1, art. 18).

Accordingly, in one embodiment, the present inhalation system comprisesa dry powder inhaler and a container for deagglomerating cohesive powderis provided, comprising a cohesive dry powder having a Carr's indexranging from 16 to 50. In one embodiment, the dry powder formulationcomprises a diketopiperazine, including, FDKP and a peptide or proteinincluding an endocrine hormone such as insulin, GLP-1, parathyroidhormone, oxyntomodulin, and others as mentioned elsewhere in thisdisclosure.

Microparticles having a diameter of between about 0.5 and about 10microns can reach the lungs, successfully passing most of the naturalbarriers. A diameter of less than about 10 microns is required tonavigate the turn of the throat and a diameter of about 0.5 microns orgreater is required to avoid being exhaled. Embodiments disclosed hereinshow that microparticles with a specific surface area (SSA) of betweenabout 35 and about 67 m²/g exhibit characteristics beneficial todelivery of drugs to the lungs such as improved aerodynamic performanceand improved drug adsorption.

Disclosed herein are also fumaryl diketopiperazine (FDKP) microparticleshaving a specific trans isomer ratio of about 45 to about 65%. In thisembodiment, the microparticles provide improved flyability.

In one embodiment, there is also provided a system for the delivery ofan inhalable dry powder comprising: a) a cohesive powder comprising amedicament, and b) an inhaler comprising an enclosure defining aninternal volume for containing a powder, the enclosure comprising a gasinlet and a gas outlet wherein the inlet and the outlet are positionedso that gas flowing into the internal volume through the inlet isdirected at the gas flowing toward the outlet. In an embodiment, thesystem is useful for deagglomerating a cohesive powder having a Carr'sindex of from 18 to 50. The system can also be useful for delivering apowder when the cohesive powder has an angle of repose from 30° to 55°.The cohesive powder can be characterized by a critical orifice dimensionof ≦3.2 feet for funnel flow or ≦2.4 feet for mass flow, a rugosity>2.Exemplary cohesive powder particles include particles comprising of FDKPcrystals wherein the ratio of FDKP isomers in the range of 50% to 65%trans:cis.

In another embodiment, the inhalation system can comprise an inhalercomprising a mouthpiece and upon applying a pressure drop of kPa acrossthe inhaler to generate a plume of particles which is emitted from themouthpiece wherein 50% of said emitted particles have a VMAD of ≦10micron, wherein 50% of said emitted particles have a VMAD of microns, orwherein 50% of said emitted particles have a VMAD of ≦4 microns.

In yet another embodiment, a system for the delivery of an inhalable drypowder comprising: a) a dry powder comprising particles composed of FDKPcrystals wherein the ratio of FDKP isomers in the range of 50% to 65%trans:cis, and a medicament; and b) an inhaler comprising a powdercontaining enclosure, the chamber comprising a gas inlet and a gasoutlet; and a housing in which to mount said chamber and defining twoflow pathways, a first flow pathway allowing gas to enter the gas inletof the chamber, a second flow pathway allowing gas to bypass the chambergas inlet; wherein flow bypassing the enclosure gas inlet is directed toimpinge upon the flow exiting the enclosure substantially perpendicularto the gas outlet flow direction.

In certain embodiments, a system for the delivery of an inhalable drypowder is provided, comprising: a) a dry powder comprising particlescomposed of FDKP crystals wherein the microparticles have a specificsurface area (SSA) of between about 35 and about 67 m²/g which exhibitcharacteristics beneficial to delivery of drugs to the lungs such asimproved aerodynamic performance and improved drug adsorption permilligram, and a medicament; and b) an inhaler comprising a powdercontaining enclosure, wherein the enclosure comprises a gas inlet and agas outlet; and a housing in which to mount said chamber and definingtwo flow pathways, a first flow pathway allowing gas to enter the gasinlet of the chamber, a second flow pathway allowing gas to bypass thechamber gas inlet; wherein flow bypassing the chamber gas inlet isdirected to impinge upon the flow exiting the enclosure substantiallyperpendicular to the gas outlet flow direction.

A system for the delivery of an inhalable dry powder is also provided,comprising: a) a dry powder comprising a medicament, and b) an inhalercomprising a powder containing cartridge, the cartridge comprising a gasinlet and a gas outlet, and a housing in which to mount the cartridgeand defining two flow pathways, a first flow pathway allowing gas toenter the gas inlet of the cartridge, a second flow pathway allowing gasto bypass the enclosure gas inlet, and a mouthpiece and upon applying apressure drop of ≧2 kPa across the inhaler plume of particles is emittedfrom the mouthpiece wherein 50% of said emitted particles have a VMAD of≦10 microns, wherein flow bypassing the cartridge gas inlet is directedto impinge upon the flow exiting the enclosure substantiallyperpendicular to the gas outlet flow direction.

Active agents for use in the compositions and methods described hereincan include any pharmaceutical agent. These can include, for example,synthetic organic compounds, proteins and peptides, polysaccharides andother sugars, lipids, inorganic compound, and nucleic acid sequences,having therapeutic, prophylactic, or diagnostic activities. Peptides,proteins, and polypeptides are all chains of amino acids linked bypeptide bonds.

Examples of active agents that can be delivered to a target or site inthe body using the diketopiperazine formulations, include hormones,anticoagulants, immunomodulating agents, vaccines, cytotoxic agents,antibiotics, vasoactive agents, neuroactive agents, anaesthetics orsedatives, steroids, decongestants, antivirals, antisense, antigens, andantibodies. More particularly, these compounds include insulin, heparin(including low molecular weight heparin), calcitonin, felbamate,sumatriptan, parathyroid hormone and active fragments thereof, growthhormone, erythropoietin, AZT, DDI, granulocyte macrophage colonystimulating factor (GM-CSF), lamotrigine, chorionic gonadotropinreleasing factor, luteinizing releasing hormone, beta-galactosidase,exendin, vasoactive intestinal peptide, and argatroban. Antibodies andfragments thereof can include, in a non-limiting manner, anti-SSX-2₄₁₋₄₉(synovial sarcoma, X breakpoint 2), anti-NY-ESO-1 (esophageal tumorassociated antigen), anti-PRAME (preferentially expressed antigen ofmelanoma), anti-PSMA (prostate-specific membrane antigen), anti-Melan-A(melanoma tumor associated antigen) and anti-tyrosinase (melanoma tumorassociated antigen).

In certain embodiments, a dry powder formulation for delivering to thepulmonary circulation comprises an active ingredient or agent, includinga peptide, a protein, a hormone, analogs thereof or combinationsthereof, wherein the active ingredient is insulin, calcitonin, growthhormone, erythropoietin, granulocyte macrophage colony stimulatingfactor (GM-CSF), chorionic gonadotropin releasing factor, luteinizingreleasing hormone, follicle stimulating hormone (FSH), vasoactiveintestinal peptide, parathyroid hormone (including black bear PTH),parathyroid hormone related protein, glucagon-like peptide-1 (GLP-1),exendin, oxyntomodulin, peptide YY, interleukin 2-inducible tyrosinekinase, Bruton's tyrosine kinase (BTK), inositol-requiring kinase 1(IRE1), or analogs, active fragments, PC-DAC-modified derivatives, orO-glycosylated forms thereof. In particular embodiments, thepharmaceutical composition or dry powder formulation comprises fumaryldiketopiperazine and the active ingredient is one or more selected frominsulin, parathyroid hormone 1-34, GLP-1, oxyntomodulin, peptide YY,heparin and analogs thereof.

In one embodiment, a method of self-administering a dry powderformulation to one's lung with a dry powder inhalation system is alsoprovided, comprising: obtaining a dry powder inhaler in a closedposition and having a mouthpiece; obtaining a cartridge comprising apremetered dose of a dry powder formulation in a containmentconfiguration; opening the dry powder inhaler to install the cartridge;closing the inhaler to effectuate movement of the cartridge to a doseposition; placing the mouthpiece in one's mouth, and inhaling oncedeeply to deliver the dry powder formulation.

In one embodiment, a method of delivering an active ingredientcomprising: a) providing dry powder inhaler containing a cartridge witha dry powder formulation comprising a diketopiperazine and the activeagent; and b) delivering the active ingredient or agent to an individualin need of treatment. The dry powder inhaler system can deliver a drypowder formulation such as insulin FDKP having a respirable fractiongreater than 50% and particles sizes less than 5.8 μm.

In still yet a further embodiment, a method of treating obesity,hyperglycemia, insulin resistance, and/or diabetes is disclosed. Themethod comprises the administration of an inhalable dry powdercomposition or formulation comprising a diketopiperazine having theformula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X isselected from the group consisting of succinyl, glutaryl, maleyl, andfumaryl. In this embodiment, the dry powder composition can comprise adiketopiperazine salt. In still yet another embodiment of the presentinvention, there is provided a dry powder composition or formulation,wherein the diketopiperazine is2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, with or without apharmaceutically acceptable carrier, or excipient.

An inhalation system for delivering a dry powder formulation to apatient's lung, comprising a dry powder inhaler configured to have flowconduits with a total resistance to flow in a dosing configurationranging in value from 0.065 to about 0.200 (√kPa)/liter per minute.

In one embodiment, a dry powder inhalation kit is provided comprising adry powder inhaler as described above, one or more medicament cartridgecomprising a dry powder formulation for treating a disorder or diseasesuch as respiratory tract disease, diabetes and obesity.

EXAMPLE 1 Measuring the Resistance and Flow Distribution of a Dry PowderInhaler—Cartridge System

Several dry powder inhaler designs were tested to measure theirresistance to flow—an important characteristic of inhalers. Inhalersexhibiting high resistance require a greater pressure drop to yield thesame flow rate as lower resistance inhalers. Briefly, to measure theresistance of each inhaler and cartridge system, various flow rates areapplied to the inhaler and the resulting pressures across the inhalerare measured. These measurements can be achieved by utilizing a vacuumpump attached to the mouthpiece of the inhaler, to supply the pressuredrop, and a flow controller and pressure meter to change the flow andrecord the resulting pressure. According to the Bernoulli principle,when the square root of the pressure drop is plotted versus the flowrate, the resistance of the inhaler is the slope of the linear portionof the curve. In these experiments, the resistance of the inhalationsystem, comprising a dry powder inhaler and cartridge as describedherein, were measured in the dosing configuration using a resistancemeasuring device. The dosing configuration forms an air pathway throughthe inhaler air conduits and through the cartridge in the inhaler.

Since different inhaler designs exhibit different resistance values dueto slight variations in geometries of their air pathways, multipleexperiments were conducted to determine the ideal interval for pressuresettings to use with a particular design. Based on the Bernoulliprinciple of linearity between square root of pressure and flow rate,the intervals for assessing linearity were predetermined for the threeinhalers used after multiple tests so that the appropriate settingscould be used with other batches of the same inhaler design. Anexemplary graph for an inhaler can be seen in FIG. 80 for an inhalationsystem depicted in FIG. 15I. The graph depicted in FIG. 80 indicatesthat the resistance of the inhalation system as depicted in FIG. 15I canbe measured with good correlation to the Bernoulli principle at flowrates ranging from about 10 to 25 L/min. The graph also shows that theresistance of the exemplary inhalation system was determined to be 0.093√kPa/LPM. FIG. 80 illustrates that flow and pressure are related.Therefore, as the slope of the line in square root of pressure versusflow graph decreases, i.e., inhalation systems exhibiting lowerresistance, the change in flow for a given change in pressure isgreater. Accordingly, higher resistance inhalation systems would exhibitless variability in flow rates for given changes in pressure provided bythe patient with a breath powered system.

The data in Tables 1 show the results of a set of experiments using theinhalers described in FIG. 50 (DPI 1), and FIGS. 15C-15K (DPI 2). Forthe dry powder inhaler 1 (DPI 1), the cartridge illustrated in design150, FIGS. 35-38, was used, and the cartridge illustrated in design 170,FIG. 39A-I was used with DPI 2. Accordingly, DPI 1 used Cartridge 1 andDPI 2 used Cartridge 2.

TABLE 1 % of Total Flow Device Total Device Through Tested ResistanceCartridge Resistance Cartridge MedTone ® 0.1099 0.368 15.28 DPI 1 0.08740.296 29.50 DPI 2 0.0894 0.234 35.56

Table 1 illustrates the resistance of the inhalation system testedherewith is 0.0874 and 0.0894 √kPa/LPM, respectively for DPI 1 and DPI2. The data show that the resistance of the inhalation system to flow isin part determined by the geometry of the air conduits within thecartridge.

EXAMPLE 2 Measurement of Particle Size Distribution Using an InhalerSystem with an Insulin Formulation

Measurements of the particle size distribution with a laser diffractionapparatus (Helos Laser Diffraction system, Sympatec Inc.) with anadaptor (MannKind Corp.) were made of a formulation of various amountsin milligram (mg) of an insulin and fumaryl diketopiperazine particlesprovided in a cartridge-inhaler system as described herewith (inhaler ofFIGS. 15C-15K with cartridge 170 shown in FIGS. 39A-39I). The device isattached at one end to a tubing, which is adapted to a flow meter (TSI,Inc. Model 4043) and a valve to regulate pressure or flow from acompressed air source. Once the laser system is activated and the laserbeam is ready to measure a plume, a pneumatic valve is actuated to allowthe powder to be discharged from the inhaler. The laser system measuresthe plume exiting the inhaler device automatically based onpredetermined measurement conditions. The laser diffraction system isoperated by software integrated with the apparatus and controlled bycomputer program. Measurements were made of samples containing differentamounts of powder and different powder lots. The measurement conditionsare as follows:

Laser measurement start trigger conditions: when ≧0.6% laser intensityis detected on a particular detector channel;

Laser measurement end trigger conditions: when ≦0.4% laser intensity isdetected on a particular detector channel;

Distance between vacuum source and inhaler chamber is approximately9.525 cm.

Multiple tests were carried out using different amounts of powders orfill mass in the cartridges. Cartridges were only used once. Cartridgeweights were determined before and after powder discharge from theinhaler to determine discharged powder weights. Measurements in theapparatus were determined at various pressure drops and repeatedmultiple times as indicated in Table 2 below. Once the powder plume ismeasured, the data is analyzed and graphed. Table 2 depicts dataobtained from the experiments, wherein CE denotes cartridge emptying(powder discharged) and Q3 (50%) is the geometric diameter of the50^(th) percentile of the cumulative powder particle size distributionof the sample, and q3(5.8 μm) denotes the percentage of the particlesize distribution smaller than 5.8 μm geometric diameter.

TABLE 2 Pressure Fill Test Drop Discharge Mass Sample Q3 q3 No. (kPa)Time (s) (mg) Size % CE (50%) (5.8 μm) 1 4 3 6.7 30 98.0 4.020 63.8 2 43 6.7 20 97.0 3.700 67.4 3 4 3 6.7 20 98.4 3.935 64.6 4 4 3 3.5 20 97.84.400 61.0 5 2 4 6.7 7 92.9 4.364 61.0 6 2 4 6.7 7 95.1 4.680 57.9 7 4 46.7 7 97.0 3.973 64.4 8 4 4 6.7 7 95.5 4.250 61.7 9 6 4 6.7 7 97.3 3.83065.3 10 6 4 6.7 7 97.8 4.156 62.2

The data in Table 2 showed that 92.9% to 98.4% of the total powder fillmass was emitted from the inhalation system. Additionally, the dataindicate that regardless of the fill mass, 50% of the particles emittedfrom the inhalation system had a geometric diameter of less than 4.7 μmas measured at the various times and pressure drops tested. Moreover,between 60% and 70% of the particles emitted had a geometric diameter ofless than 5.8 μm.

FIG. 81 depicts data obtained from another experiment in which 10 mg ofpowder fill mass was used. The graph shows the particle sizedistribution of the sample containing particles of a formulationcomprising insulin and fumaryl diketopiperazine resulted in 78.35% ofthe measured particles had a particle size of ≦5.8 μm. The laserdetected 37.67% optical concentration during the measurement duration of0.484 seconds at the above measurement conditions. The data show thatthe inhalation system effectively deagglomerates the insulin-FDKPformulation to small sizes over a relevant and lower range of userinhalation capacities, i.e., pressure drops. These small geometric sizesfor this cohesive (Carr's index=36%) formulation are believed to berespirable.

EXAMPLE 3 Measurement of Powder Discharge from a Cartridge as a Measureof Inhalation System Performance

The experiments were conducted using the inhalation system describedherewith using multiple inhaler prototypes depicted in FIGS. 15C-15Kwith cartridge 170 prototypes as shown in FIGS. 39A-39I. Multiplecartridges were used with each inhaler. Each cartridge was weighed in anelectronic balance prior to fill. The cartridges were filled with apredetermined mass of powder, again weighed and each filled cartridgewas placed in an inhaler and tested for efficiency of emptying a powderformulation, i.e., Technosphere® Insulin (insulin-FDKP; typically 3-4 Uinsulin/mg powder, approximately 10-15% insulin w/w) powder batches.Multiple pressure drops were used to characterize the consistency ofperformance. Table 3 depicts results of this testing using 35 cartridgedischarge measurements per inhaler. In the data in Table 3, all testswere carried out using the same batch of a clinical grade insulin-FDKPpowder. The results show that relevant user pressure drops, ranging from2 through 5 kPa demonstrated a highly efficient emptying of the powderfrom the cartridge.

TABLE 3 Pressure Test Drop Discharge Fill Mass Sample Mean % CE No.(kPa) Time (s) (mg) Size % CE SD 1 5.00 3.00 3.08 35 99.42 0.75 2 5.003.00 3.00 35 98.11 1.11 3 5.00 3.00 6.49 35 99.49 0.81 4 5.00 3.00 6.5535 99.05 0.55 5 5.00 2.00 6.57 35 98.69 0.94 6 5.00 2.00 6.57 35 99.331.03 7 4.00 3.00 6.47 35 98.15 1.15 8 4.00 3.00 6.50 35 99.37 0.46 94.00 3.00 3.28 35 98.63 0.93 10 4.00 3.00 3.18 35 98.63 1.48 11 4.002.00 6.61 35 92.30 3.75 12 4.00 2.00 6.58 35 98.42 1.71 13 3.00 3.006.55 35 92.91 5.04 14 3.00 3.00 6.56 35 98.88 0.63 15 3.00 2.00 6.56 3596.47 3.19 16 3.00 2.00 6.59 35 99.49 0.54 17 3.00 1.00 6.93 35 98.062.37 18 3.00 1.00 6.95 35 98.74 0.67 19 3.00 1.00 3.12 35 97.00 1.06 203.00 1.00 3.15 35 96.98 0.99 21 2.00 1.00 6.53 35 97.24 1.65 22 2.001.00 6.49 35 98.48 2.27

EXAMPLE 4 Measurement of Predictive Deposition by Andersen CascadeImpaction

The experiments were conducted using an Andersen Cascade Impactor tocollect stage plate powder deposits during a simulated dose deliveryusing flow rates of 28.3 LPM. This flow rate resulted in a pressure dropacross the inhalation system (DPI plus cartridge) of approximately 6kPa. Depositions on the plate stages were analyzed gravimetrically usingfilters and electronic balances. Fill weights of a cohesive powder in 10mg, 6.6 mg and 3.1 mg fill mass were evaluated for inhalation systemperformance. Each impaction test was conducted with five cartridges. Thecumulative powder mass collected on stages 2-F was measured inaccordance with aerodynamic particle sizes less than 5.8 μm. The ratioof the collected powder mass to the cartridge fill content wasdetermined and is provided as percent respirable fraction (RF) over thefill weight. The data is presented in Table 4.

The data show that a respirable fraction ranging from 50% to 70% wasachieved with multiple powder batches. This range represents anormalized performance characteristic of the inhalation system.

The inhaler system performance measurements were repeated 35 times witha different cartridge. Fill mass (mg) and discharge time (seconds) weremeasured for each inhaler cartridge system used. Additionally, thepercent of respirable fraction, i.e., particles suitable for pulmonarydelivery, in the powder was also measured. The results are presented inTable 4 below. In the table, the RF/fill equals the percent of particleshaving a size (≦5.8 μm) that would travel to the lungs in the powder; CEindicates cartridge emptying or powder delivered; RF indicatesrespirable fraction. In Table 4, Test Nos. 1-10 were conducted using asecond batch of a clinical grade of the insulin-FDKP powder, but thetest powder for 11-17 used the same powder as the tests conducted andpresented in Table 3.

TABLE 4 Pressure Discharge Fill Drop Time Mass Sample Mean % RF/ % RF/No. (kPa) (s) (mg) Size % CE Fill Delivered 1 6.4 8 9.7 5 98.9 56.6 58.32 6.4 8 9.9 5 88.8 53.7 60.4 3 6.4 8 8.2 5 97.5 54.9 56.9 4 6.4 8 6.7 598.4 56.8 58.1 5 6.4 8 10.0 5 89.2 60.4 67.8 6 6.4 8 9.6 5 99.3 53.553.9 7 6.4 8 9.6 5 98.2 57.3 58.4 8 6.4 8 9.6 5 99.0 56.9 57.5 9 6.4 89.6 5 95.4 59.3 62.1 10 6.4 8 6.6 5 99.4 61.7 62.1 11 6.4 8 6.6 5 99.659.0 59.2 12 6.4 8 6.6 5 96.5 62.6 64.8 13 6.4 8 6.6 5 98.7 59.8 60.6 146.4 8 3.1 5 99.5 66.3 66.6 15 6.4 8 3.1 5 99.7 70.7 70.9 16 6.4 8 3.1 597.6 65.9 67.5 17 6.4 8 3.1 5 98.2 71.6 73.0

The data above show that the present inhalation system comprising a drypowder inhaler and a cartridge containing a cohesive powder, i.e.,TECHNOSPHERE® Insulin (FDKP particles comprising insulin) can dischargeeffectively almost all of the powder content, since greater than 85% andin most cases greater than 95% of the total powder content of acartridge at variable fill masses and pressure drops were obtained withconsistency and significant degree of emptying. The Andersen cascadeimpaction measurements indicated that greater than 50% of the particlesare in the respirable range wherein the particles are less than 5.8 μmand ranging from 53.5% to 73% of the total emitted powder.

EXAMPLE 5 Rugosity of Technosphere® Insulin (TI)

The rugosity is the ratio of the actual specific surface area of theparticle to that for an equivalent sphere. The specific surface area ofa sphere is:

${SSA}_{sphere} = {\frac{\pi\; d_{eff}^{2}}{\rho\frac{\pi}{6}d_{eff}^{3}} = \frac{6}{\rho\; d_{eff}}}$where d_(eff)=1.2 μm is the surface-weighted diameter of TI particlesfrom Sympatec/RODOS laser diffraction measurements.An average sphere with the same density as the TI particle matrix (1.4g/cm³) would therefore have an SSA of

$\begin{matrix}{{SSA}_{sphere} = \frac{6}{\rho\; d_{eff}}} \\{= {\frac{6}{\left( {1.4\frac{g}{{cm}^{3}}} \right)\left( {1.2 \times 10^{- 6}\mspace{11mu} m} \right)}\left( \frac{m^{3}}{10^{6}\mspace{14mu}{cm}^{3}} \right)}} \\{= {3.6\mspace{14mu} m^{2}\text{/}g}}\end{matrix}$Thus for TI particles with specific surface area (SSA) of approximately40 m²/g

${Rugosity} = {\frac{({SSA})_{TI}}{({SSA})_{sphere}} = {\frac{40\mspace{14mu} m^{2}\text{/}g}{3.6\mspace{14mu} m^{2}\text{/}g} \approx 11.}}$

For similarly sized particles with specific surface area of 50 or 60m²/g the rugosity would be roughly 14 and 16 respectively.

EXAMPLE 6 Geometric Particle Size Analysis of Emitted Formulations byVolumetric Median Geometric Diameter (VMGD) Characterization

Laser diffraction of dry powder formulations emitted from dry powderinhalers is a common methodology employed to characterize the level ofde-agglomeration subjected to a powder. The methodology indicates ameasure of geometric size rather than aerodynamic size as occurring inindustry standard impaction methodologies. Typically, the geometric sizeof the emitted powder includes a volumetric distribution characterizedby the median particle size, VMGD. Importantly, geometric sizes of theemitted particles are discerned with heightened resolution as comparedto the aerodynamic sizes provided by impaction methods. Smaller sizesare preferred and result in greater likelihood of individual particlesbeing delivered to the pulmonary tract. Thus, differences in inhalerdeagglomeration and ultimate performance can be easier to resolve withdiffraction. In these experiments, an inhaler as specified in EXAMPLE 3and a predicate inhaler are tested with laser diffraction at pressuresanalogous to actual patient inspiratory capacities to determine theeffectiveness of the inhalation system to de-agglomerate powderformulations. Specifically, the formulations included cohesivediketopiperazine powders with an active insulin loaded ingredient andwithout. These powder formulations possessed characteristic surfaceareas, isomer ratios, and Carr's indices. Reported in Table 5 are a VMGDand an efficiency of the container emptying during the testing. FDKPpowders have an approximate Carr's index of 50 and TI powder has anapproximate Carr's index of 40.

TABLE 5 pressure Inhaler % drop sample VMGD system powder trans SSA(kPa) size % CE (micron) DPI 2 FDKP 56 55 4 15 92.5 6.800 MedTone ® FDKP56 55 4 30 89.5 21.200 DPI 2 FDKP + 56 45 4 30 98.0 4.020 active DPI 2FDKP + 56 45 4 20 97.0 3.700 active DPI 2 FDKP + 56 45 4 20 98.4 3.935active DPI 2 FDKP + 56 45 4 20 97.8 4.400 active MedTone ® FDKP + 56 454 10 86.1 9.280 active MedTone ® FDKP + 56 45 4 10 92.3 10.676 activeDPI 2 FDKP + 56 45 2 7 92.9 4.364 active DPI 2 FDKP + 56 45 2 7 95.14.680 active DPI 2 FDKP + 56 45 4 7 97.0 3.973 active DPI 2 FDKP + 56 454 7 95.5 4.250 active DPI 2 FDKP + 56 56 4 10 99.6 6.254 active DPI 2FDKP + 56 14 4 10 85.5 4.037 active MedTone ® FDKP + 56 56 4 20 89.712.045 active MedTone ® FDKP + 56 14 4 20 37.9 10.776 active DPI 2FDKP + 54 50 4 10 97.1 4.417 active DPI 2 FDKP + 54 44 4 10 96.0 4.189active DPI 2 FDKP + 56 35 4 10 92.0 3.235 active DPI 2 FDKP + 50 34 4 1093.2 5.611 active DPI 2 FDKP + 66 33 4 10 79.0 4.678 active DPI 2 FDKP +45 42 4 10 93.2 5.610 active DPI 2 FDKP + 56  9 4 10 78.9 5.860 active

These data in Table 5 show an improvement in powder deagglomeration overa predicate inhaler system as compared to the inhaler system describedherein. Diketopiperazine formulations with surface areas ranging from14-56 m²/g demonstrated emptying efficiencies in excess of 85% and VMGDless than 7 microns. Similarly, formulations possessing an isomer ratioranging from 45-66% trans demonstrated improved performance over thepredicate device. Last, performance of the inhaler system withformulations characterized with Carr's indices of 40-50 were shown to beimproved over the predicate device as well. In all cases, the reportedVMGD values were below 7 microns.

EXAMPLE 7 Relationship Between Trans Isomer Content and RF/Fill

Microparticles were manufactured from FDKP and insulin. FDKP wasdissolved in aqueous NH₄OH to form a solution. A feed stream of thissolution was combined with a feed stream of an aqueous HOAc solution ina high shear mixer to form an aqueous suspension of microparticles.

The FDKP feed solution was prepared with about 2.5 wt % FDKP, about 1.6wt % concentrated NH₄OH (about 28 to about 30 wt % NH₃) and about 0.05wt % polysorbate 80. The acetic acid feed solution was prepared at about10.5 wt % GAA and about 0.05 wt % polysorbate 80. Both feed solutionswere filtered through an about 0.2 μm membrane prior to use.

Equal amounts (by mass) of each feed solution were pumped through aDual-Feed Sonolator™ equipped with the #5 orifice (0.0011 sq. inch). Theminor pump was set to 50% for equal flow rates of each feed stream andthe feed pressure was about 2000 psi. The receiving vessel contained DIwater equal to the mass of either feed solution (e.g. 4 kg FDKP feedsolution and 4 kg HOAc feed solution would be pumped through theSonolator™ into the receiving vessel containing 4 kg of DI water).

The resulting suspension was concentrated and washed by means oftangential flow filtration using a 0.2 m² PES membrane. The suspensionswere first concentrated to about 4% solids then diafiltered with DIwater and finally concentrated to about 16% nominal solids. The actualpercent solids of the washed suspension was determined by “loss ondrying.”

Insulin stock solutions were prepared containing about 10 wt % insulin(as received) in a solvent comprising about 2 wt % HOAc in DI water andsterile filtered. The stock solution was filtered through a 0.22 μmfilter prior to use. Based on the solids content of the suspension, theappropriate amount of stock solution was added to the mixed suspension.The resulting microparticle/insulin was then adjusted from a pH of about3.6 to a pH of about 4.5 using an ammonia solution.

The microparticle/insulin suspension was then flash frozen bypelletizing (cryo-granulating) into liquid nitrogen. The ice pelletswere lyophilized until the drying was complete.

The respirable fraction (RF/fill) of bulk powders is a measure ofaerodynamic microparticle size distribution and is determined by testingwith the Andersen cascade impacter. To obtain RF/fill values, cartridgesare filled with bulk powder and discharged through a MEDTONE® inhaler at30 L/min. The powder collected on each inhaler stage is weighed and thetotal powder collected is normalized to the total amount filled in thecartridges. Accordingly, RF/fill is powder collected on those stages ofthe impacter representing the respirable fraction divided by powderloaded into cartridges.

As shown in FIG. 82, FDKP powders with acceptable aerodynamicperformance measured as RF/fill have been produced from FDKP with aslittle as 45% trans isomer (FIG. 82). Powders containing more than 65%trans-FDKP tended to have lower and more variable RF/fill.

This study determined the upper end of the trans isomer content rangewith beneficial aerodynamic properties. The next sections describeexperiments conducted to evaluate processing conditions that cangenerate the specified isomer contents.

EXAMPLE 8 Saponification Solvent

Experiments were conducted to determine the effect, if any, of thesaponification solvent on % trans isomer FDKP (FIG. 83).

A mixture of 004 and 590 mL of reaction solvent (see Table 5) was heatedto about 57° C. After the reaction temperature had stabilized, about 50%NaOH solution was added dropwise via addition funnel over about 60minutes. The reaction was held for about 30 minutes after the NaOHaddition was complete and then filtered to remove any unreacted solids.The filtrate was acidified with acetic acid to a pH of about 5 and theresulting solids isolated by filtration, washed with water and acetone,dried in a vacuum oven, and analyzed by HPLC to determine cis and transisomer content.

Accordingly, five different solvent systems ranging from aqueous (Table5, A) to organic (Table 5, E) were evaluated. In general, the resultsshowed that as methanol content in the methanol/water solvent systemincreased, the percent of trans FDKP also increased, althoughsaponification in 100% methanol gave FDKP with low trans isomer contentand was complicated by low FDKP solubility in methanol:

TABLE 5 Affect of water:methanol Solvent Ratio in Step 5 on FDKP IsomerContent Sample ID Water:Methanol Ratio (v:v) % Trans FDKP A 4:0 51 B 3:153 C 2:2 55 D 1:3 78 E 0:4 33

EXAMPLE 9 Recrystallization Conditions

FDKP can be recrystallized from a TAA (solvent)/GAA (anti-solvent)mixture (FIG. 86; step 6). Controlled process parameters were evaluatedto characterize this recrystallization process and its effects on FDKPisomer contents. The effect of each parameter on the isomer contentvaried as a function of reaction yield. That is, low product recoveryresulted in elevated trans isomer levels because cis FDKP has a greatersolubility in TFA. These yield effects complicated data interpretation,so it was difficult to characterize the effect of a given parameter on %trans FDKP alone. However, the data suggest that an about 40 to about65% yield is necessary to meet the about 45 to about 65% trans FDKPrange. Accordingly, data points that did not meet this required minimumyield were excluded.

The following experiments used the following procedure unless aparameter was modified to examine its effect on FDKP isomer contents andyield.

A reactor was charged with crude FDKP (about 75 g) and TFA (about 250mL) and stirring was initiated. The suspension was heated to reflux(about 80 to about 85° C.) and held for about 10 minutes or until allsolids were dissolved. The mixture was cooled to below about 60° C.Glacial acetic acid (about 375 mL) was added to the solution. Themixture was cooled and held for a minimum of about 6 hours at about 10to about 20° C. The precipitated product was filtered and washed withGAA (3×about 100 mL), acetone (3×about 100 mL) and water (1×about 100mL). The product was dried at about 55° C. under vacuum (about 22 toabout 25 in. Hg) for about 12 to about 18 hours.

Initially, four factors were tested including solvent quantity,anti-solvent quantity, crystallization time and crystallizationtemperature. A solvent quantity of about 2.68 or about 3.34 mL/g FDKPprovided acceptable % trans isomer. At around 6.68 mL solvent/g FDKP, anunacceptably high trans isomer content was produced. The amount ofanti-solvent did not significantly affect % trans FDKP isomer content atup to 5.0 mL/g FDKP. Reducing anti-solvent quantity from the controlquantity substantially produced a % trans FDKP above the desired range.

In these experiments crystallization time did not significantly affecttrans FDKP isomer content at up to about 6 hours. Isomer content % transFDKP) fell outside the about 45 to about 65% range at the high (35° C.)and low (0° C.) crystallization temperatures tested.

Subsequent experiments supported these findings. FIG. 87 shows a surfacedepicting FDKP isomer content, measured as % trans FDKP, as a functionof solvent:anti-solvent ratio (TFA:GAA) and crystallization temperature.Over the ranges tested in these experiments the values for % trans FDKPvaried from 59-75%. The data suggest that trans FDKP is within thedesired range at a low solvent ratio (0.43) and high crystallizationtemperatures (25° C.). Predicted values for trans FDKP in this area ofthe response surface are 58-60%. These observations suggest that using acrystallization temperature of 25° C. could be advantageous.

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the devices, techniquesand methods disclosed herein elucidate representative embodiments thatfunction well in the practice of the present disclosure. However, thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsthat are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe following specification and attached claims are approximations thatmay vary depending upon the desired properties sought to be obtained bythe present invention. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques. Notwithstanding that the numerical ranges andparameters setting forth the broad scope of the invention areapproximations, the numerical values set forth in the specific examplesare reported as precisely as possible. Any numerical value, however,inherently contains certain errors necessarily resulting from thestandard deviation found in their respective testing measurements.

The terms “a” and “an” and “the” and similar referents used in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. Recitation of ranges of values herein is merely intended toserve as a shorthand method of referring individually to each separatevalue falling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and “and/or.”

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is hereindeemed to contain the group as modified thus fulfilling the writtendescription of all Markush groups used in the appended claims.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on those preferred embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects those of ordinary skill in the art toemploy such variations as appropriate, and the inventors intend for theinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above citedreferences and printed publications are herein individually incorporatedby reference in their entirety.

Further, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

The invention claimed is:
 1. A drug delivery system comprising aninhaler, a powder container, comprising fumaryl diketopiperazine (FDKP)microparticles comprising a trans-FDKP isomer content of about 45% toabout 65% and a drug, wherein the aerodynamic performance of themicroparticles is improved as compared to fumaryl diketopiperazinemicroparticles having a trans isomer content outside of said transisomer content of about 45% to about 65%; and wherein in use about 10%to 70% of an air flow exiting the inhaler and entering a user passesthrough the powder container and about 90% to 30% of said air flowbypasses the powder container.
 2. The drug delivery system of claim 1wherein the FDKP microparticles have a trans-FDKP isomer content ofabout 45% to about 56%.
 3. The drug delivery system of claim 1 whereinsaid powder container comprises a unit dose cartridge.
 4. The drugdelivery system of claim 1 wherein the FDKP microparticles comprise adrug comprising insulin, GLP-1, heparin, calcitonin, felbamate,parathyroid hormone and fragments thereof, oxyntomodulin, growthhormone, erythropoietin, AZT, DDI, G-CSF, lamotrigine, chorionicgonadotropin releasing factor, luteinizing releasing hormone,β-galactosidase or Argatroban.
 5. The drug delivery system of claim 1having a resistance to flow of about 0.065 to about 0.200 (√kPa)/literper minute.
 6. The drug delivery system of claim 4 wherein the drug isinsulin.
 7. The drug delivery system of claim 6 wherein the insulincontent of the FDKP microparticles is about 3 to about 4 U/mg.
 8. Amethod of treating an insulin-related disorder comprising providing, forself-administration, the drug delivery system of claim 1 to administerinsulin to a person in need thereof.
 9. A drug delivery systemcomprising an inhaler, a powder container comprising FDKP microparticleshaving improved aerodynamic performance that have been prepared by aprocess comprising determining the trans-FDKP isomer content; whereinthe microparticles have a trans-FDKP isomer content of about 45% toabout 65% and the aerodynamic performance of the microparticles isimproved as compared to fumaryl diketopiperazine microparticles having atrans isomer content outside of said trans isomer content of about 45%to about 65%; and wherein in use about 10% to 70% of an air flow exitingthe inhaler and entering a user passes through the powder container andabout 90% to 30% of said air flow bypasses the powder container.
 10. Thedrug delivery system of claim 9 comprising FDKP microparticles having atrans-FDKP isomer content of about 50% to about 63%.
 11. The drugdelivery system of claim 9 comprising FDKP microparticles having atrans-FDKP isomer content of about 45% to about 56%.
 12. The drugdelivery system of claim 9 having a resistance to flow of approximately0.065 to about 0.200 (IkPa)/liter per minute.
 13. The drug deliverysystem of claim 1 wherein the FDKP microparticles are prepared by aprocess comprising recrystallizing FDKP from a solvent, then formingmicroparticles, wherein the trans-FDKP content of the microparticles isabout 45% to about 65%.
 14. The drug delivery system of claim 13 whereinthe FDKP microparticles have a trans-FDKP isomer content of about 50% toabout 65%.
 15. The drug delivery system of claim 13 wherein the FDKPmicroparticles have a trans-FDKP isomer content of about 54% to about65%.
 16. The drug delivery system of claim 4 having a manufacturingspecification in a range of about 53% to about 63% trans-FDKP isomercontent, based upon the total content of FDKP.
 17. The drug deliverysystem of claim 15 wherein the FDKP microparticles have a trans-FDKPisomer content of about 54% to about 63%.
 18. The drug delivery systemof claim 17 wherein the FDKP microparticles have a trans-FDKP isomercontent of about 54% to about 56%.